Fall-Related Adverse Events of Anti-Epileptic Drugs used for Neuropathic Pain in Older Adults: A systematic Review and Meta-Analysis

Fall-Related Adverse Events of Anti-Epileptic Drugs used for Neuropathic Pain in Older Adults: A systematic Review and Meta-Analysis | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Systematic Review Fall-Related Adverse Events of Anti-Epileptic Drugs used for Neuropathic Pain in Older Adults: A systematic Review and Meta-Analysis Arun Vamadevan, Dr Vijesh Vijayan, Dr. Fellisha Marwein, Nishad Yoosuf This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6945897/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background: Older adults are at elevated risk of falls, especially when prescribed AED (AEDs) for neuropathic pain. The sedative and neuropsychiatric effects of these agents contribute significantly to fall-related morbidity. However, existing studies often lack stratification by age and dose. Objective: To systematically evaluate the incidence and drug-specific risk of falls and fall-related adverse events (AEs) in older adults prescribed AEDs for neuropathic pain. Methods: A systematic search was performed across PubMed, Scopus, CINAHL, ScienceDirect, and Cochrane Library databases up to May 2025. Studies were selected using PICOS criteria and included RCTs and controlled cohort studies reporting on AED-related AEs among participants aged ≥60 years. The methodological quality was assessed using RoB 2, ROBINS-I, and GRADE frameworks. Meta-analyses were performed using logit event rates and fixed-effects modeling via Comprehensive Meta-Analysis v3.7. Publication bias was evaluated using Begg’s and Egger’s tests. Results: Twenty-three studies met inclusion criteria. The pooled logit event rate for falls was –1.693 (95% CI: –1.993 to –1.393), corresponding to a 15.5% incidence. Gabapentin showed the lowest fall risk (~10%), while pregabalin and carbamazepine were associated with higher rates of dizziness (up to 21.6%), sedation (~15.5%), and ataxia (~17.8%). Heterogeneity was low (I² = 0–22.3%) across outcomes. Conclusion: AEDs carry a clinically significant fall risk in older adults, with dose-dependent patterns. Gabapentin may present a safer profile, while pregabalin and carbamazepine warrant cautious use and monitoring. These findings inform individualized prescribing and fall prevention strategies in geriatric neuropathic pain management. PROSPERO: CRD420251048827 Clinical Pharmacology Geriatrics & Gerontology Antiepileptic drugs older adults Falls Systematic review Meta-analysis Adverse drug reactions Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Figure 8 Figure 9 Key Points Antiepileptic drugs such as gabapentin, and pregabalin are commonly prescribed for neuropathic pain in older adults, but their safety profiles in this population are not well established. This systematic review and meta-analysis synthesised data from 23 studies and found consistent associations between specific antiepileptic drugs and fall-related adverse events, including dizziness, sedation, and impaired coordination. Gabapentin was associated with a comparatively lower risk of fall-related adverse events, suggesting it may be a safer option among antiepileptic drugs for older adults when used for neuropathic pain. The risk of these adverse outcomes varied across individual antiepileptic drugs, suggesting a need for drug-specific risk-benefit assessments in older patients. These findings support more cautious, individualised prescribing in older people with neuropathic pain, alongside routine fall-risk monitoring to improve medication safety. 1. Introduction Neuropathic pain is a common and disabling condition among older adults, with prevalence rates ranging from 7–10% in community-dwelling populations and even higher among institutionalized older Adults individuals ( 1 ). Initial treatments for neuropathic pain frequently include antiepileptic drugs (AEDs) such as gabapentin, pregabalin, and carbamazepine, which act by modulating calcium channels and sodium conductance in nociceptive pathways ( 2 ). However, these medications also exert significant central nervous system (CNS) effects, resulting in common adverse events such as dizziness, sedation, ataxia, and somnolence—factors strongly associated with increased fall risk in older adults ( 3 ). Falls are the leading cause of injury, hospitalization, and loss of independence in people aged ≥ 65, with roughly 30% of older adults experiencing at least one fall annually( 4 ). Importantly, medications are among the most modifiable risk factors for falls, and polypharmacy involving CNS-active drugs such as AEDs and antidepressants is particularly hazardous ( 5 ). Despite this, older adults are frequently underrepresented or excluded from randomized controlled trials (RCTs), especially in dose-finding studies, resulting in an evidence gap regarding drug safety in real-world geriatric populations ( 6 ). Although observational studies have linked AEDs to increased fall risk, with odds ratios as high as 2.55 ( 7 ), these studies often lack dosage stratification and are susceptible to confounding. A recent review by Zia et al. (2017)( 8 ) emphasized the urgent need for high-quality studies that delineate drug-specific and dose-dependent risks in older populations. In the absence of such data, clinicians face significant uncertainty in balancing analgesic efficacy with fall-related harms( 9 ). Most existing literature either aggregates data across diverse CNS-active drug classes or fails to stratify by age and dose, limiting clinical applicability( 10 ). This lack of granular evidence leaves prescribers without robust guidance on which AEDs may pose higher risks at certain doses in geriatric populations( 11 ). This study aims to address critical knowledge gaps by systematically evaluating and quantifying the incidence of fall-related adverse events in older adults receiving AEDs for neuropathic pain. Given the heightened vulnerability of older populations to falls—often triggered by CNS-active medications—this analysis focuses specifically on identifying drug- and dose-dependent risk patterns. Using data from randomized controlled trials and controlled observational studies, the review quantifies the incidence of key fall-associated adverse events, including dizziness, somnolence, sedation, vertigo, and ataxia. Importantly, it not only examines aggregate risk but also stratifies by individual AEDs and their corresponding dosages to determine differential safety profiles. By doing so, the study seeks to inform safer prescribing practices, especially in geriatric care settings where polypharmacy and comorbidities complicate treatment decisions. The findings are intended to support clinicians in balancing analgesic efficacy with fall risk, ultimately guiding more individualized and risk-aware pharmacologic management of neuropathic pain in older adults. 2. Methods This study was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines ( 22 ) for conducting systematic reviews and meta-analyses. Compliance with the principles of the Declaration of Helsinki further reinforced the ethical foundation of this review. This review exclusively analyzed secondary data from existing studies and, therefore, qualifies for exemption from informed consent or institutional review board approval. The study protocol was registered on the PROSPERO online database with the registration number CRD420251048827 2.1 Search Strategy: A comprehensive and systematic literature search was conducted by two authors (AV and VV) across five electronic databases PubMed, Cochrane Library, Scopus, ScienceDirect and CINAHL covering studies published up to May 2025 as described in Table 1 . The search strategy was developed using a combination of MeSH terms and free-text keywords related to AED (e.g., “gabapentin,” “pregabalin,” “carbamazepine,” “lamotrigine”), adverse events (e.g., “falls,” “dizziness,” “ataxia,” “somnolence,” “sedation,” “vertigo”), and older populations (e.g., “elderly,” “aged,” “older adults”). Boolean operators (AND/OR) were used to structure search strings, with database-specific syntax adjustments. Filters were applied to restrict results to human studies involving participants aged ≥ 60 years. Only English-language publications were included. Duplicates were removed using automated reference management tools, followed by manual screening. Records lacking free full-text availability were excluded. Titles and abstracts were screened for relevance, and full-texts were assessed against predefined inclusion criteria. Reference lists of included studies were also manually searched to identify additional eligible studies. Table 1 Detailed database search strategy with keywords and Boolean operators used across MEDLINE, Embase, and CENTRAL Database Search Strategy String Scopus ( "antiepileptic drugs" AND elderly ) CINAHL ("antiepileptic drugs" OR AEDs OR gabapentin OR pregabalin OR carbamazepine OR lamotrigine OR oxcarbazepine OR lacosamide) AND ("older adults" OR elderly OR aged) AND (falls OR "fall risk" OR dizziness OR vertigo OR ataxia OR somnolence OR sedation) AND ("randomized controlled trial" OR clinical trial) ScienceDirect "antiepileptic" AND "falls" AND "older adults" PubMed ("gabapentin"[Supplementary Concept] OR "gabapentin"[All Fields] OR "gabapentin"[MeSH Terms] OR "gabapentine"[All Fields] OR "gabapentin s"[All Fields] OR ("pregabalin"[Supplementary Concept] OR "pregabalin"[All Fields] OR "pregabalin"[MeSH Terms] OR "pregabalin s"[All Fields] OR "pregabaline"[All Fields]) OR ("carbamazepine"[Supplementary Concept] OR "carbamazepine"[All Fields] OR "carbamazepin"[All Fields] OR "carbamazepine"[MeSH Terms] OR "carbamazepines"[All Fields] OR "carbamazepine s"[All Fields]) OR ("lamotrigin"[All Fields] OR "lamotrigine"[Supplementary Concept] OR "lamotrigine"[All Fields] OR "lamotrigine"[MeSH Terms] OR "lamotrigine s"[All Fields]) OR ("oxcarbazepin"[All Fields] OR "oxcarbazepine"[Supplementary Concept] OR "oxcarbazepine"[All Fields] OR "oxcarbazepine"[MeSH Terms]) OR ("lacosamide"[Supplementary Concept] OR "lacosamide"[All Fields] OR "lacosamide"[MeSH Terms])) AND ("accidental falls"[MeSH Terms] OR ("accidental"[All Fields] AND "falls"[All Fields]) OR "accidental falls"[All Fields] OR "falling"[All Fields] OR "falls"[All Fields] OR "fallings"[All Fields] OR ("dizziness"[MeSH Terms] OR "dizziness"[All Fields] OR "dizzy"[All Fields] OR "vertigo"[MeSH Terms] OR "vertigo"[All Fields]) OR ("ataxia"[MeSH Terms] OR "ataxia"[All Fields] OR "ataxias"[All Fields]) OR ("vertigo"[MeSH Terms] OR "vertigo"[All Fields] OR "vertigos"[All Fields] OR "vertigoes"[All Fields]) OR ("sleepiness"[MeSH Terms] OR "sleepiness"[All Fields] OR "somnolence"[All Fields] OR "somnolent"[All Fields]) OR ("sedate"[All Fields] OR "sedated"[All Fields] OR "sedating"[All Fields] OR "sedation"[All Fields] OR "sedations"[All Fields])) Cochrane Library ("antiepileptic drugs" OR gabapentin OR pregabalin OR carbamazepine OR lamotrigine OR oxcarbazepine OR lacosamide) AND ("older adults" OR elderly OR aged) AND ("neuropathic pain") AND (falls OR dizziness OR ataxia OR vertigo OR somnolence OR sedation) IN Trials 2.2 Study selection: Study selection was performed using the PICOS (Participants, Intervention, Comparisons, Outcomes, and Study Design) framework to define inclusion and exclusion criteria. The inclusion and exclusion criteria for this systematic review were defined using the PICOS framework to ensure methodological rigor and relevance to the research objectives. Population criteria included studies involving older adults aged > 50 years, reflecting the population most vulnerable to antiepileptic drug (AED)-associated adverse events (AEs) such as falls. Interventions were restricted to AEDs prescribed for neuropathic pain, including gabapentin, pregabalin, carbamazepine, oxcarbazepine, lamotrigine, lacosamide, levetiracetam, and related agents. Comparators included placebo, usual care, or other AEDs, allowing for assessment of relative safety profiles. Outcomes required clear reporting of fall-related AEs including falls, dizziness, ataxia, vertigo, somnolence, or sedation. Study design inclusion was limited to randomized controlled trials (RCTs), cohort studies, and controlled observational studies that provided extractable quantitative data. Studies were excluded if they did not report on older populations or failed to stratify data by age, focused on other indications such as epilepsy without mention of the adverse events relating to fall, assessed non-AED interventions, did not report on falls or neuropsychiatric AEs relevant to fall risk, or were reviews, editorials, letters, case reports, or non-English publications. These criteria ensured that the selected studies were both clinically relevant and methodologically sound for evaluating the risk of falls related to AEDs in the older adults. 2.3 Data Collection and Quality Evaluation: Data collection and quality evaluation were carried out independently by two reviewers, who screened the titles and abstracts of studies in Mendeley Cite based on the inclusion criteria. Full texts of potentially eligible studies were reviewed, with disagreements resolved through decisioning by a blinded third author (NY). Data were extracted into a pre-tested Microsoft Excel sheet for consistency, documenting key details such as author, year, study design, country, diagnosis, sample size, mean age, interventions and measured outcomes. Methodological rigor and potential biases were also documented to ensure systematic data collection and analysis. The methodological quality of the included studies was rigorously evaluated using established tools tailored to study design. For randomized controlled trials (RCTs), the Revised Cochrane Risk of Bias tool (RoB 2)( 12 ) was applied to assess bias across domains such as randomization, deviations from intended interventions, missing outcome data, measurement of outcomes, and selection of reported results. Non-randomized studies were assessed using the ROBINS-I (Risk Of Bias In Non-randomised Studies - of Interventions)( 13 ) tool, which evaluates confounding, selection bias, classification of interventions, deviations, missing data, measurement of outcomes, and reporting bias. Each study was independently appraised by two reviewers, with discrepancies resolved through consensus. Additionally, the overall certainty of the evidence for each outcome was graded using the GRADE (Grading of Recommendations, Assessment, Development, and Evaluations)( 14 ) framework, which considers study limitations, inconsistency, indirectness, imprecision, and publication bias. This comprehensive evaluation ensured the reliability and interpretability of the synthesized evidence. 2.4 Statistical Analysis: The statistical analysis for this meta-analysis was conducted using Comprehensive Meta-Analysis (CMA) software version 3.7. Pooled estimates of logit event rates and corresponding standard errors were calculated using a fixed-effects model, appropriate due to the generally low heterogeneity observed across studies. The primary measure of effect was the logit event rate, which allowed for consistent transformation of event proportions across studies, particularly when event rates were near 0 or 1. Standard errors and 95% confidence intervals were calculated for each logit event rate. Subgroup analyses were conducted based on drug type and dose to evaluate variation in adverse events such as falls, dizziness, somnolence, sedation, vertigo, and ataxia among older patients treated with AED. A Z-test determined the statistical significance of pooled outcomes, with p < 0.05 considered significant. Heterogeneity among studies was quantified using the Q statistic, p-value, and I² index, with I² values below 30% considered low. Publication bias was assessed through both Begg’s rank correlation test and Egger’s regression intercept test. In cases where asymmetry was detected in funnel plots, potential bias was further explored through sensitivity analyses. This rigorous approach ensured a statistically robust synthesis of evidence, supporting reliable conclusions for clinical application. 3. Results 3.1 Study Selection: The PRISMA flowchart illustrates the systematic process of literature identification, screening, and selection applied in this study. A total of 4,447 records were initially retrieved from five electronic databases: PubMed (n = 2,326), Cochrane Library (n = 137), Scopus (n = 1,018), ScienceDirect (n = 898), and CINAHL (n = 68). Following the removal of duplicates (n = 2,407) and records lacking free full-text access (n = 253), 1,787 records were screened. An automated exclusion tool removed 873 records based on title and abstract relevance. The remaining 914 records were sought for full-text retrieval, but 542 could not be accessed or retrieved, leaving 372 reports for full eligibility assessment. Among these, 286 were excluded for not specifically addressing older adult populations, 33 due to unrelated interventions, and 30 for lacking data on falls or related adverse events. Ultimately, 23 studies met the inclusion criteria and were incorporated into the final review. 3.2 Study Characteristics: The included studies encompass a diverse range of randomized controlled trials and observational designs evaluating the effects of antiepileptics and CNS-active medications on outcomes such as neuropathic pain, psychiatric symptoms, and fall risk in older adults. Sample sizes varied widely—from as small as 8 participants ( 15 ) to over 41,000 subjects ( 16 ) with most studies focusing on older adults aged more than 50 years and above. Diagnoses addressed included chronic sciatica, painful diabetic neuropathy, epilepsy, bipolar depression, and dementia-related agitation. Interventions spanned a broad pharmacologic spectrum, including gabapentin, pregabalin, lamotrigine, carbamazepine, lacosamide, mirtazapine, and combinations with B vitamins or antidepressants. Several studies employed head-to-head comparisons or combination therapy strategies. Common findings included gabapentin’s superior tolerability over pregabalin ( 17 ), and a consistent association between CNS drugs and increased fall risk across multiple cohort studies ( 18 , 19 ). Despite methodological variability, the studies collectively support the clinical relevance of medication-induced adverse effects, especially in geriatric populations, and underscore the importance of individualized, risk-balanced pharmacologic management. Table 2 Characteristics of included studies evaluating AED-related fall risk in older adults Study Country Sample Size Mean Age Diagnosis Interventions Key Findings Robertson et al, 2018 ( 20 ) Australia 18 57 ± 16.5 Chronic Sciatica Gabapentin vs Pregabalin Gabapentin superior in pain reduction and fewer adverse events compared to pregabalin. Richards et al, 2025( 21 ) USA 147 83.4 ± 9.1 RLS with dementia Gabapentin enacarbil vs Placebo Reduced nighttime agitation; trend toward more falls in the gabapentin group (P = 0.066). Saetre et al, 2009( 22 ) Norway 108 ≥ 65 Newly diagnosed epilepsy Carbamazepine vs Lamotrigine No significant ECG changes; both drugs tolerated well in older Adults. Brodie et al, 1999( 23 ) UK/Europe 150 77 Newly diagnosed epilepsy Lamotrigine vs Carbamazepine Lamotrigine had fewer adverse events and better continuation than carbamazepine. Sajatovic et al, 2011( 24 ) USA 57 66.5 ± 6.7 Bipolar depression Lamotrigine (augmentation) Improvement in depression and function; some adverse events including unsteady gait. Roose et al, 2003( 25 ) USA 119 ≥ 70 Depression Mirtazapine (15–45 mg/day) Effective in depression; common AEs were falls (18%) and somnolence (12%). Alvarado et al, 2016( 26 ) Mexico 270 > 50 Painful diabetic neuropathy Gabapentin + B1/B12 vs Pregabalin Comparable efficacy; less vertigo with gabapentin/B1/B12 (P = 0.014); lower gabapentin doses needed for pain relief. Saetre et al 2007( 27 ) Norway/Multicenter 185 ≥ 65 Newly diagnosed epilepsy Lamotrigine (25–500 mg/day), Carbamazepine SR (100–2000 mg/day) LTG and CBZ had similar effectiveness; CBZ had higher seizure freedom, LTG better tolerability. Freynhagen et al 2005( 28 ) Multicenter 338 62.7 ± 10.6 DPN or PHN (neuropathic pain) Pregabalin (flexible: 150–600 mg/day or fixed: 300–600 mg/day) Both regimens reduced pain and sleep interference; dizziness and somnolence common AEs. Dworkin et al 2009( 29 ) USA 87 ≥ 50 Acute pain in herpes zoster Gabapentin (1200–1800 mg/day), CR-oxycodone, placebo Oxycodone reduced pain more than placebo; gabapentin had modest effect; common AEs included constipation. Jensen-Dahm et al 2011( 15 ) USA 8 65 Acute herpes zoster pain Pregabalin (150 mg single dose) 33% pain reduction vs 14% placebo; well tolerated; effects on allodynia not significant. Holbech et al (2015)( 30 ) Multicenter (EU) 73 20–85 years Painful polyneuropathy Imipramine 75 mg/day vs Pregabalin 300 mg/day vs Combination vs Placebo Combination significantly more effective than either monotherapy but had more adverse events. Sommer et al (2009)( 31 ) Germany 103 83 Agitation/aggression in dementia Oxcarbazepine vs Placebo No significant difference in agitation/aggression; slight trend favoring oxcarbazepine. Wymer et al (2009)( 32 ) International NR 58 Painful diabetic neuropathy Lacosamide 200 mg/d, 400 mg/d, 600 mg/d vs Placebo Lacosamide 400 mg/d showed optimal efficacy/tolerability; 600 mg/d had high AE dropout rate. Tesfaye et al (2022)( 33 ) UK (13 sites) 130 Mean: 60s Diabetic peripheral neuropathic pain (DPNP) A-P, P-A, D-P pathways combining amitriptyline, duloxetine, pregabalin All had similar efficacy; combination better than monotherapy if pain relief suboptimal. Dustin et al, 2006( 16 ) USA 41,102 (20,551 cases, 20,551 controls) > 65 Fall-related outpatient visits vs nonspecific chest pain Analysis of CNS, CVS, and MSS drugs prescribed CNS drugs (e.g., antidepressants, anticonvulsants, antipsychotics) more common in fall patients. CVS drugs more common in controls. Highlighted medication-related fall risk. Luukinen et al, 1995( 34 ) Finland 1016 ≥ 70 Recurrent falls in home-dwelling older Adults Community-based observation and fall history Prior falls, peripheral neuropathy, psychotropics, and slow gait identified as predictors of recurrent falls. Tromp et al, 1998( 35 ) Netherlands 1469 > 60 (Born before 1931) Falls, recurrent falls, fractures Population-based cohort analysis Impaired mobility, analgesics, and antiepileptics predicted recurrent falls. Fractures predicted by inactivity, female gender, and prior fractures. Kelly et al, 2003( 36 ) Netherlands 1469 > 60 Recurrent falls and fractures Baseline interview with follow-up over 38 months Similar to Tromp et al: identified analgesics and inactivity as strong predictors. Recurrent falls occurred in 15% of the cohort. Mayo et al, 1989( 37 ) Canada 402 (201 cases, 201 controls) > 60 Falls in rehabilitation hospital Retrospective case-control from admission records Stroke, incontinence, anticonvulsants, and topical eye meds predicted falls. Risk model validated in second cohort year. Ensrud et al. 2002( 18 ) USA 8,127 women ≥ 65 years Community-dwelling older women CNS-active drugs: benzodiazepines, antidepressants, anticonvulsants, narcotics Use of benzodiazepines (OR: 1.51), antidepressants (OR: 1.54), and anticonvulsants (OR: 2.56) significantly increased risk of frequent falls. Narcotics not associated. Masud et al. 2013( 19 ) Denmark 4,696 men Median: 66.3 years Men aged 60–75 years, general population CNS drugs: opiates, antidepressants, anxiolytics, SSRIs, TCAs Opiates (OR: 2.4), antidepressants (OR: 2.8), SSRIs (OR: 3.1), TCAs (OR: 2.2), and antiepileptics (OR: 2.8) significantly associated with falls. Titler et al. 2011( 38 ) USA 10,187 hospitalizations ≥ 60 years Hospitalized older adults Medical/pharmacy/nursing treatments; CNS meds; fall prevention interventions Antidepressants, antipsychotics, benzodiazepines, restraints, and neurologic monitoring linked to falls. RN skill mix, ulcer care, and pain management inversely related. 3.3 Risk of Bias Assessment: The risk of bias for the 15 randomized controlled trials (RCTs) included in this analysis was evaluated using the RoB 2 tool. Most RCTs demonstrated a low overall risk of bias, particularly in domains related to randomization, adherence to intended interventions, and outcome measurement. Studies by Robertson et al. (2018)( 20 ), Saetre et al. (2007, 2009)( 22 , 26 ), and Tesfaye et al. (2022)( 33 ) were rigorously designed with appropriate allocation concealment, blinding, and complete outcome reporting. A few studies, such as Sajatovic et al. (2011)( 24 ) and Wymer et al. (2009)( 32 ), showed “some concerns” due to moderate dropout rates or adverse event-related attrition, potentially influencing outcome reliability. Holbech et al. (2015) also raised concern due to higher dropout in the combination arm. Despite these limitations, most studies maintained methodological robustness, ensuring reliable efficacy and safety comparisons of antiepileptic and CNS-active medications in older adults. For the eight observational studies and cohort designs, the ROBINS-I tool was applied to assess bias. Most prospective cohort studies, including those by Luukinen et al. (1995)( 34 ), Tromp et al. (1998)( 35 ), and Ensrud et al. (2002)( 18 ), were deemed low risk across domains due to well-defined participant selection, standardized outcome assessment, and control of key confounders. Conversely, retrospective studies such as Dustin et al. (2006)( 16 ) and Mayo et al. (1989)( 37 ) were rated as having moderate bias due to limitations in confounder adjustment, potential selection bias, and missing data handling. Cross-sectional data from Masud et al. (2013)( 19 ) and retrospective registry-based data in Titler et al. (2011)( 38 ) also indicated moderate bias due to measurement and reporting variability. These findings underscore the need for cautious interpretation of results from non-randomized studies, although they provide valuable real-world insights into fall risk associations with CNS medication use in the older Adults. 3.4 GRADE assessment: The GRADE assessment of included studies revealed a moderate to high certainty of evidence for most randomized controlled trials (RCTs), particularly those evaluating antiepileptic and neuropathic pain medications in older populations. Studies such as Saetre et al. (2007), Freynhagen et al. (2005)( 28 ), and Tesfaye et al. (2022)( 33 ) demonstrated high methodological rigor, consistent results, and direct clinical applicability, thereby achieving a high certainty rating. Conversely, trials with small sample sizes, high dropout rates, or imprecision in outcome estimates—such as those by Jensen-Dahm et al. (2011)( 15 ) and Roose et al. (2003)( 25 )—were downgraded to low or moderate certainty. Among observational studies, the certainty of evidence was generally moderate, as seen in large-scale cohort studies like Ensrud et al. (2002)( 18 ) and Masud et al. (2013)( 19 ), which provided robust associations between CNS-active drugs and fall risk. However, studies such as Mayo et al. (1989)( 37 ) and Titler et al. (2011)( 38 ) were rated low due to potential confounding and imprecision. Overall, the GRADE findings reinforce the reliability of key conclusions while also highlighting areas requiring cautious interpretation due to methodological limitations. Table 3 GRADE quality assessment of evidence for adverse event outcomes in older adults using antiepileptic drugs Study Outcome Risk of Bias Inconsistency Indirectness Imprecision Publication Bias Certainty of Evidence Robertson et al., 2018 Pain reduction Low Low Low Serious (small sample) Low Moderate Richards et al., 2025 Agitation reduction Low Low Low Serious (high AE rate) Low Moderate Saetre et al., 2009 ECG safety Low Low Low Low Low High Brodie et al., 1999 AED tolerability Some concerns Low Low Serious (older trial) Low Moderate Sajatovic et al., 2011 Depression response Some concerns Moderate Low Serious Low Low Roose et al., 2003 Depression symptoms Some concerns Moderate Serious Serious Low Low Alvarado et al., 2016 Neuropathic pain Low Low Low Low Low High Saetre et al., 2007 Seizure control Low Low Low Low Low High Freynhagen et al., 2005 DPN/PHN pain Low Low Low Low Low High Dworkin et al., 2009 Acute zoster pain Low Low Low Serious Low Moderate Jensen-Dahm et al., 2011 Acute zoster pain Low Serious (n = 8) Low Serious Low Low Holbech et al., 2015 Polyneuropathy pain Low Low Low Serious (dropouts) Low Moderate Sommer et al., 2009 Agitation Low Low Low Serious (underpowered) Low Moderate Wymer et al., 2009 DPN pain Low Low Low Low Low High Tesfaye et al., 2022 DPN pain Low Low Low Low Low High Dustin et al., 2006 Falls vs drug class Moderate Low Low Low Low Low Luukinen et al., 1995 Recurrent falls Low Low Low Low Low Moderate Tromp et al., 1998 Recurrent falls/fractures Low Low Low Low Low Moderate Mayo et al., 1989 Hospital falls Moderate Low Serious Serious Low Low Ensrud et al., 2002 CNS meds & falls Low Low Low Low Low Moderate Masud et al., 2013 CNS meds in older men Low Low Low Low Low Moderate Titler et al., 2011 Hospital falls & interventions Moderate Low Low Serious Low Low 3.5 Incidence on Falls: The Forest Plot in Fig. 4 evaluated the incidence of falls among older patients receiving AEDs for neuropathic pain, synthesizing data from eight studies and subgrouping by drug type. The overall pooled logit event rate was − 1.693 (SE = 0.153; 95% CI: -1.993 to -1.393), which corresponds to an estimated fall incidence of approximately 15.5%. The heterogeneity across studies was low (Q = 6.83; df = 7; p = 0.45; I² = 0%), suggesting consistency in effect estimates. Among subgroups, Gabapentin was represented by three studies ( 29 )( 21 ), yielding a pooled logit of -2.20 (SE = 0.32), equating to a lower fall incidence (~ 10%) and moderate heterogeneity (I² = 32.8%). Pregabalin, analyzed in two studies ( 15 )( 33 ) showed a higher logit rate of -1.53 (SE = 0.68), suggesting ~ 18% fall risk, with no significant heterogeneity (I² = 0%). Lamotrigine ( 24 ), Mirtazapine ( 25 ), and Oxcarbazepine ( 31 ) were each evaluated in single studies, with logit event rates of -1.85, -1.52, and − 1.44 respectively, translating to a fall incidence ranging between 14% and 18%. The consistency in directionality across AEDs highlights a clinically meaningful risk of falls, particularly relevant in geriatric populations with neuropathic pain. Notably, gabapentin was associated with a comparatively lower risk, suggesting it may be a safer option in fall-prone older adults individuals. These findings emphasize the importance of fall-risk assessment and individualized drug selection in older adults, especially when initiating or titrating AED therapy for neuropathic pain. Further studies should explore dose-response relationships and mechanisms underlying differential fall risks across AEDs. 3.6 AE relating to Falls: 3.6.1 Incidence of Dizziness: The Forest plot in Fig. 5 revealed that dizziness is a prevalent adverse event (AE) among older patients prescribed AEDs for neuropathic pain, with an overall fixed-effect logit event rate of − 1.483 (SE = 0.066), translating to an incidence of approximately 18.4%. The analysis demonstrated low heterogeneity (I² = 22.3%), indicating consistency across studies. Drug-specific analysis showed that Lacosamide had the highest dizziness incidence (~ 21.6%) with significant heterogeneity (I² = 90.2%), reflecting dose-related variability between 200 mg and 600 mg regimens. Gabapentin (300–3600 mg/day) also demonstrated a high incidence (~ 19.7%) with moderate heterogeneity (I² = 60.6%), likely due to wide dosing variations. In contrast, drugs like Lamotrigine (25–500 mg/day) and Carbamazepine (300–2000 mg/day) showed lower dizziness rates (~ 16–17%) and minimal heterogeneity (I² = 0%), suggesting more stable safety profiles. Pregabalin (150–600 mg/day) had a pooled incidence of ~ 20.6% with consistent results across studies (I² = 0%). Single-study estimates for Levetiracetam, Mirtazapine, and Oxcarbazepine showed dizziness incidences ranging from 13–18%. The findings indicate a dose-dependent pattern, where higher or more rapidly titrated doses (notably for Gabapentin and Lacosamide) are associated with increased dizziness. Clinically, this underscores the importance of individualized dosing and cautious titration, especially in frail older adults at risk of falls. Agents like Lamotrigine and Carbamazepine may be preferable when aiming to minimize vestibular side effects. These results highlight the need for fall-prevention strategies and close monitoring of patients, particularly when initiating or up-titrating AED therapy in geriatric neuropathic pain management. 3.6.2 Incidence of Somnolence: This meta-analysis in Fig. 6 examined the incidence of somnolence—a critical adverse event (AE) linked to fall risk—in older patients receiving AED for neuropathic pain. Thirteen studies were included, stratified by AED class and dosage. The overall pooled logit event rate was − 1.667 (SE = 0.079), which corresponds to an approximate somnolence event rate of 15.9% . This indicates that somnolence is a clinically significant and relatively common AE in this population. The statistical association was robust ( Z = − 20.99, p < 0.001 ), and overall heterogeneity was low ( I² = 16.7%, Q = 14.41, df = 12, p = 0.275 ), suggesting consistent results across studies. Subgroup analysis by drug and dose showed notable trends. Carbamazepine (300–2000 mg) had a pooled logit of − 1.66 with mild heterogeneity ( I² = 41.5% ). Gabapentin (600–3600 mg) and lamotrigine (75–500 mg) had similar effects (logit ~–1.55 to − 1.60) and negligible heterogeneity. Pregabalin (300–600 mg) showed more variability ( I² = 85.9% ), possibly due to differing study designs and dose responses. Single-study data for levetiracetam (3000 mg), oxcarbazepine (2400 mg), and mirtazapine (15–45 mg) also demonstrated strong associations with somnolence. These findings underscore the importance of careful AED selection and dose titration in the older adults, where even modest somnolence increases the risk of falls and associated morbidity. Clinicians should consider fall-prevention strategies and prefer agents with lower sedative burden. These results highlight the need for individualized risk–benefit assessments, especially in frail older Patients with polypharmacy 3.6.3 Incidence of Sedation: The meta-analysis in Fig. 7 examined the incidence of sedation as an adverse event (AE)—a key contributor to fall risk—in older patients using AED (s) for neuropathic pain. The overall pooled logit event rate was − 1.700 (SE = 0.158, p < 0.0001), translating to an estimated sedation rate of approximately 15.5%. The low heterogeneity (Q = 7.60, df = 7, p = 0.37; I² = 0%) suggests consistency across the eight included studies. Subgroup analysis by drug type and dosage revealed clinically relevant differences in sedation risk. For Gabapentin, sedation risk was observed across doses from 600 mg to 2400 mg, with the highest incidence noted at 1800 mg (logit event rate − 1.96, SE = 0.57, p = 0.0005, Dworkin et al.) and 1800 mg again in Mikkelsen et al. (logit − 1.81, SE = 0.57, p = 0.0013). At 600 mg (Richards et al. 2025), although the logit rate was − 1.64 (SE = 0.32), statistical significance was higher (p = 3.3×10⁻⁷), indicating even lower doses warrant caution. For Pregabalin, the highest sedation incidence was seen at 600 mg in Tesfaye et al. 2022 (logit − 2.31, SE = 0.34, p = 7.4×10⁻¹²). Notably, 150 mg (Jensem-dahm 2011) showed a high logit rate (–2.59) but with wide confidence intervals, likely due to small sample size. Oxcarbazepine, evaluated at 900 mg, also showed significant sedation (logit − 1.10, SE = 0.32, p = 0.0006). These findings underscore the need for careful dose selection and monitoring, especially at or above 600–1800 mg for Gabapentin and 600 mg for Pregabalin. Clinicians must weigh analgesic benefit against sedation-induced fall risk in older patients, ensuring individualized therapy and fall-prevention strategies. 3.6.4 Vertigo Incidence: The Forest Plot in Fig. 8 assessed the incidence of vertigo—a key contributor to fall risk—as an adverse event in older patients receiving AEDs for neuropathic pain. The overall pooled logit event rate was − 2.442 (SE = 0.134, p < 0.0001), corresponding to an estimated vertigo incidence of approximately 8%. The analysis demonstrated no significant heterogeneity across the nine included studies (Q = 4.62, df = 8, p = 0.80; I² = 0%), suggesting consistent results across AED types and dosages. Carbamazepine at 2000 mg (Brodie et al., 1999) showed a logit event rate of − 2.11, translating to the highest vertigo incidence (≈ 11.1%), with a strong statistical signal (p = 3.6×10⁻¹¹). For Gabapentin, the 3600 mg dose (Alvarado et al., 2016) had a notably high event rate (logit − 2.42; ≈8.2%), whereas 2400 mg (Robertson et al., 2018) showed a lower and non-significant effect (p = 0.08), suggesting a possible threshold for increased risk beyond 3000 mg. Lacosamide at both 600 mg and 200 mg (Wymer et al., 2009) had a combined logit of − 2.61 (≈ 7.2%), showing a dose-independent consistent risk. Lamotrigine at 500 mg (Brodie et al., 1999) showed an event rate of approximately 10.5%. Among all, Pregabalin 600 mg (Alvarado et al., 2016) showed the lowest logit of − 3.18 (≈ 4%), while the combined doses from three studies yielded a pooled rate of − 2.61 (≈ 6.7%). Clinically, these findings suggest that higher doses of Carbamazepine (2000 mg), Gabapentin (≥ 3600 mg), and Lamotrigine (500 mg) are associated with higher vertigo incidence in older patients. Careful dose titration and vertigo monitoring are essential to minimize fall-related morbidity. 3.6.5 Incidence of Ataxia: Figure 9 shows the results on meta-analysis, which evaluated the incidence of ataxia—a critical adverse event (AE) contributing to fall risk—in older patients treated with AEDs for neuropathic pain. The overall pooled logit event rate was − 1.875 (SE = 0.170, p < 0.0001), which corresponds to an ataxia incidence of approximately 13.3% (using inverse logit transformation). This indicates a clinically meaningful rate of motor coordination impairment attributable to AED use in this population. Notably, heterogeneity was low and non-significant across the five included studies (Q = 5.22, df = 4, p = 0.27; I² = 23.4%), suggesting robust and consistent findings. Carbamazepine (2000 mg) showed a significant association with ataxia (logit − 1.61, p = 1.38×10⁻⁹), translating to an incidence of ~ 17.8%. Similarly, Lamotrigine (500 mg) reported a logit of − 1.77 (p = 1.54×10⁻⁵; ≈14.5% incidence), and Oxcarbazepine (900 mg) yielded a logit of − 1.71 (p = 9.17×10⁻⁶; ≈15.3% incidence). Among Pregabalin doses, although both 300 mg and 600 mg were evaluated, the pooled logit rate was − 2.59 (p = 4.83×10⁻¹³), corresponding to a lower incidence (~ 7%), suggesting that Pregabalin may be better tolerated with respect to ataxia. Clinically, these findings underscore the need for careful dose selection and monitoring when prescribing AEDs to older adults. Higher doses of Carbamazepine, Lamotrigine, and Oxcarbazepine were associated with greater ataxia risk, which can significantly increase fall-related morbidity. Therefore, Pregabalin at moderate doses may be a safer alternative, although individualized risk–benefit assessments remain crucial. 3.7 Publication Bias: Publication bias across the outcomes falls, dizziness, somnolence, sedation, and vertigo was assessed using Begg and Mazumdar’s rank correlation test and Egger’s regression intercept and visually represented as Funnel plots in Supplementary Figs. 1–6. For fall outcome, Kendall’s tau-b was − 0.321 (p = 0.265), and Egger’s intercept was − 0.889 (95% CI: -2.79 to 1.01; p = 0.296), suggesting no significant publication bias. Similarly, dizziness outcome assessment showed Kendall’s tau-b of -0.208 (p = 0.176) and Egger’s intercept of -0.874 (95% CI: -2.14 to 0.39; p = 0.164), again indicating no evidence of bias. For somnolence outcome, Begg’s tau-b was − 0.244 (p = 0.246) and Egger’s intercept was − 1.474 (95% CI: -4.31 to 1.36; p = 0.277), also non-significant. Sedation outcome demonstrated Kendall’s tau-b of -0.393 (p = 0.174) and Egger’s intercept of -0.591 (95% CI: -3.02 to 1.83; p = 0.573), with no bias indicated. Finally, vertigo outcome showed the strongest evidence against bias, with Kendall’s tau-b of -0.028 (p = 0.917) and Egger’s intercept of -0.196 (95% CI: -2.26 to 1.87; p = 0.829). Notably, only vertigo’s Trim and Fill suggested missing studies (n = 2), prompting a re-estimation of the pooled effect, which remained robust (from − 2.442 to -2.552). For all other outcomes, the Trim and Fill analysis showed no missing studies. Overall, none of the Egger or Begg tests reached statistical significance, and no corrections were needed except for vertigo, where the adjusted estimate was still within the confidence bounds, supporting the reliability of the meta-analytic findings. These results suggest minimal to no publication bias across the outcomes, strengthening the validity of the observed adverse event rates. 4. Discussion This comprehensive meta-analysis evaluated the incidence of key AEs related to falls in older patients prescribed AED for neuropathic pain. Six major AEs—falls, dizziness, somnolence, sedation, vertigo, and ataxia—were systematically analyzed across 15 studies using fixed-effect and subgroup meta-analytical models, with additional stratification by drug type and dosage. Although the study defines 'older adults' as individuals aged 50 years and above, this threshold was selected to capture a broader at-risk population commonly affected by neuropathic pain and medication-related adverse effects. While this may differ from traditional geriatric age cutoffs (≥ 65 years), the inclusion of this transitional age group enhances the clinical relevance of the findings, particularly in settings where age-related physiological vulnerability begins earlier. The overall pooled logit event rate for falls was − 1.693 (SE = 0.153), indicating a fall incidence of approximately 15.5%, with Gabapentin showing the lowest risk (~ 10%) and Pregabalin showing a higher fall incidence (~ 18%). Dizziness was the most common AE, with a pooled incidence of 18.4% (logit − 1.483), and Lacosamide exhibiting the highest dizziness risk (~ 21.6%) along with substantial heterogeneity (I² = 90.2%). Somnolence and sedation had comparable pooled incidence rates of ~ 15.9% and ~ 15.5%, respectively, with highest sedation observed for Pregabalin 600 mg and Gabapentin 1800 mg. Vertigo incidence was ~ 8% (logit − 2.442), with higher rates associated with Carbamazepine and high-dose Gabapentin (≥ 3600 mg). Ataxia was noted in ~ 13.3% of cases, most significantly with Carbamazepine, Lamotrigine, and Oxcarbazepine. Across all outcomes, heterogeneity was generally low to moderate, suggesting consistent results. With fall incidence estimated at approximately 15.5% across RCTs, the results align with observational evidence highlighting AED-related fall risk in older adults. For example, Ensrud et al. (2002) identified a 2.56-fold increased risk of frequent falls among women using anticonvulsants in a large U.S. cohort, while Dustin et al. (2006) similarly reported significantly higher CNS drug use—including AEDs—among fall-related outpatient visits in veterans. Masud et al. (2013) extended these findings to men, revealing 2–3-fold increased fall risks with anticonvulsants, SSRIs, and TCAs. Our RCT-based analysis echoes these associations, particularly noting elevated dizziness and sedation rates with gabapentin and pregabalin, and higher vertigo and ataxia rates at upper therapeutic doses of carbamazepine and lamotrigine. Notably, the pooled RCT data suggest a somewhat lower incidence of vertigo (~ 8%) and ataxia (~ 13%) than observational estimates, potentially due to stricter trial inclusion criteria, more controlled dosing, and shorter follow-up periods. Nonetheless, the convergence of evidence reinforces AEDs as key pharmacologic contributors to fall risk, especially when combined with polypharmacy and comorbid frailty. Furthermore, the more favorable AE profiles observed with pregabalin in terms of ataxia, and with lamotrigine in terms of dizziness, corroborate prior reports suggesting improved tolerability with newer AEDs. The findings from this meta-analysis are strongly corroborated by extensive observational evidence demonstrating consistent associations between antiepileptic drug use and fall risk in older populations. Multiple systematic reviews have confirmed that AED use in ambulatory older adults leads to significantly increased fall risk, with relative risks ranging from 1.29 to 1.62 and odds ratios from 1.75 to 6.2 ( 7 , 39 ). The meta-analysis findings align particularly well with large-scale epidemiological studies, including Ensrud et al.'s prospective cohort of over 8,000 women, which documented a 2.56-fold increased risk of frequent falls among anticonvulsant users ( 18 ). Similarly, Masud et al.'s cross-sectional study of Danish men aged 60–75 years reported odds ratios of 2.8 for falls and 2.6 for recurrent falls with AED use ( 19 ). The observed drug-specific patterns are also supported by real-world evidence, with gabapentin and pregabalin showing dose-dependent associations with altered mental status and falls in haemodialysis patients, where gabapentin demonstrated 50–55% higher hazards of falls in the highest dose categories( 40 ). Furthermore, observational studies in diabetic peripheral neuropathy patients have confirmed that anticonvulsant use significantly increases fall risk (HR 1.34, 95% CI 1.18–1.51)( 41 ), while polypharmacy studies demonstrate that fall risk is particularly elevated when AEDs are combined with other CNS-active medications in frail older adults populations. A prior systematic review reported an odds ratio of 1.88 (95% CI: 1.02–3.49) for falls among community-dwelling older adults using AEDs, reinforcing the robustness of our pooled estimate of fall incidence at 15.5% across AED types( 42 ). Similarly, de Vries et al. confirmed that both opioids and AEDs are significantly associated with increased fall risk, validating our subgroup findings of drug-specific and dose-dependent fall-related adverse event (AE) profiles ( 43 ). Notably, our analysis identified dizziness, somnolence, and sedation as frequent AEs—mirroring clinical reports where such symptoms are most commonly linked to gabapentin and pregabalin( 44 ). The heterogeneity observed in lacosamide, and gabapentin subgroups may be attributable to such dose variability. For example, pregabalin at 300 mg/day or higher has been shown to result in withdrawal due to AEs in 32% of patients, compared to only 5% in placebo arms( 45 )—a pattern closely aligned with our observed dropout-linked AEs. Collectively, these converging lines of evidence underscore the need for individualized prescribing, incorporating careful dose titration, fall-risk screening, and shared decision-making in older patients receiving AEDs for neuropathic pain. The findings of our meta-analysis are highly consistent with those reported by Seppälä et al. (2018)( 7 ), reinforcing the association between AED use and increased fall risk in older adults. Seppälä et al.’s ( 7 ) pooled analysis demonstrated a significant association between AEDs and fall risk (adjusted OR 1.55; 95% CI: 1.25–1.92), closely aligning with our estimated fall incidence of approximately 15.5% derived from pooled logit event rates. Notably, both studies highlight opioids and AEDs as high-risk classes, underscoring the critical need for cautious prescribing in geriatric populations. Our dose-stratified analyses further expand on these findings, identifying elevated risks of dizziness, sedation, and ataxia—particularly at higher AED doses such as gabapentin (≥ 2400 mg) and pregabalin (600 mg). While Seppälä et al. ( 7 ) identified substantial heterogeneity across studies, our low heterogeneity supports consistency in specific AED-related adverse event patterns. Together, these findings emphasize the importance of individualized prescribing and comprehensive fall-risk assessment in older adults receiving these medications. This study, while comprehensive, has several limitations that warrant consideration. First, despite the inclusion of high-quality randomized controlled trials and observational studies, heterogeneity in study design, population characteristics, and dosing regimens may have introduced residual confounding. The use of varied definitions and reporting formats for adverse events such as dizziness, vertigo, and ataxia across studies may have also affected the comparability and precision of pooled estimates. Second, many included studies reported adverse events only as secondary outcomes, potentially underestimating the true incidence due to underreporting or limited follow-up durations. Third, while the fixed-effects model was appropriate due to overall low heterogeneity, it may not fully capture true variability in drug response across different older adults subgroups, particularly those with polypharmacy or cognitive impairment. Fourth, the analysis was limited to published English-language literature, introducing potential publication and language bias. Future research should aim to explore real-world evidence through prospective cohort studies and pragmatic trials focusing on fall-related outcomes as primary endpoints. Dose-response meta-analyses and subgroup evaluations stratified by frailty status, renal function, and co-medication use are essential to understand the individualized risks of AED-related falls. Additionally, mechanistic studies exploring pharmacokinetic and pharmacodynamic changes in the older Adults could inform safer prescribing. Finally, the development and validation of fall-risk prediction tools incorporating drug profiles and geriatric syndromes may support more tailored and safer therapeutic decisions for neuropathic pain management in older adults. These efforts are critical for minimizing harm and improving quality of life in this vulnerable population. 5. Conclusion This comprehensive meta-analysis underscores the significant risk of falls and associated neuropsychiatric adverse events in older patients prescribed AED for neuropathic pain management. The pooled logit event rate for falls was − 1.693 (SE = 0.153; 95% CI: − 1.993 to − 1.393), corresponding to a fall incidence of approximately 15.5%, with low heterogeneity (I² = 0%), indicating consistency across studies. Among specific AEDs, gabapentin demonstrated the lowest fall incidence (~ 10%) while carbamazepine and lamotrigine were associated with higher risks (~ 17–18%). Dizziness, a leading predictor of fall-related morbidity, was reported in 18.4% of patients overall, with particularly high rates in lacosamide (~ 21.6%) and gabapentin (~ 19.7%) groups. Similarly, the incidence of somnolence and sedation were notable at ~ 15.9% and ~ 15.5%, respectively, further reinforcing the role of AEDs in fall pathophysiology among older adults. Vertigo and ataxia, though less frequently reported (8% and 13.3%, respectively), were significantly associated with high doses of carbamazepine, lamotrigine, and gabapentin. Importantly, the findings demonstrated dose-dependent increases in adverse event rates, particularly for gabapentin (> 1800 mg), pregabalin (> 300 mg), and lacosamide (600 mg), supporting the need for cautious titration and individualized therapy. These results highlight the need for routine fall-risk assessments when initiating or escalating AED therapy in geriatric populations. Clinicians should favor agents with lower sedative profiles, apply conservative titration schedules, and consider non-pharmacologic strategies where possible. Ultimately, the study reinforces the critical balance between analgesic benefit and harm mitigation, advocating for a patient-centered approach to neuropathic pain management in older adults. Declarations Ethics approval and consent to participate Not applicable. This systematic review and meta-analysis did not involve the use of human participants, human data, or human tissue. Consent for publication Not applicable. The manuscript does not contain data from any individual person. Availability of data and materials All data generated or analysed during this study are included in this published article and its supplementary files. Forest plots, risk of bias assessments, and GRADE evidence tables are available within manuscript. Competing interests The authors declare that they have no competing interests. Funding No specific funding was received for this work. The review was conducted as part of the authors’ academic and clinical research development. Authors' contributions AV (Arun Vamadevan, BSc, MPH, PGDTHS): Conceptualisation, Methodology, Data curation, Formal analysis, Investigation, Writing – Original Draft, Project administration, Supervision, Validation. VV (Dr. Vijesh Vijayan, MD, MRCP, DTM&H): Conceptualisation, Methodology, Data curation, Formal analysis, Investigation, Writing – Original Draft, Project administration, Supervision, Validation. FM : Literature search, screening, and manuscript review. NY (Nishad Yoosuf, MSc): Data extraction, quality appraisal, and manuscript review. All authors read and approved the final manuscript. Arun Vamadevan and Dr. Vijesh Vijayan contributed equally and share first authorship. Author order does not reflect seniority. Acknowledgements We would like to thank the NIHR Clinical Research Facility at Liverpool University Hospitals NHS Foundation Trust for supporting the lead author's academic development. We also acknowledge institutional training support from the University of Salford. Authors’ information AV : Postgraduate Researcher (PhD), University of Salford , Matron, NIHR Clinical Research Facility, Liverpool University Hospitals NHS Foundation Trust;. 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Pain [Internet]. 2005 Jun [cited 2025 Jun 11];115(3):254–63. Available from: https://pubmed.ncbi.nlm.nih.gov/15911152/ Dworkin RH, Barbano RL, Tyring SK, Betts RF, McDermott MP, Pennella-Vaughan J et al (2009) A randomized, placebo-controlled trial of oxycodone and of gabapentin for acute pain in herpes zoster. Pain [Internet]. Apr [cited 2025 Jun 11];142(3):209–17. Available from: https://pubmed.ncbi.nlm.nih.gov/19195785/ Holbech JV, Bach FW, Finnerup NB, Brøsen K, Jensen TS, Sindrup SH (2015) Imipramine and pregabalin combination for painful polyneuropathy: A randomized controlled trial. Pain [Internet]. May 1 [cited 2025 Jun 11];156(5):958–66. Available from: https://pubmed.ncbi.nlm.nih.gov/25719617/ Sommer OH, Aga O, Cvancarova M, Olsen IC, Selbaek G, Engedal K Effect of oxcarbazepine in the treatment of agitation and aggression in severe dementia. Dement Geriatr Cogn Disord [Internet]. 2009 Mar [cited 2025 Jun 11];27(2):155–63. Available from: https://pubmed.ncbi.nlm.nih.gov/19182483/ Wymer JP, Simpson J, Sen D, Bongardt S (2009) Efficacy and safety of lacosamide in diabetic neuropathic pain: An 18-week double-blind placebo-controlled trial of fixed-dose regimens. Clinical Journal of Pain [Internet]. [cited 2025 Jun 11];25(5):376–85. Available from: https://pubmed.ncbi.nlm.nih.gov/19454870/ Tesfaye S, Sloan G, Petrie J, White D, Bradburn M, Julious S et al Comparison of amitriptyline supplemented with pregabalin, pregabalin supplemented with amitriptyline, and duloxetine supplemented with pregabalin for the treatment of diabetic peripheral neuropathic pain (OPTION-DM): a multicentre, double-blind, randomised crossover trial. The Lancet [Internet]. 2022 Aug 27 [cited 2025 Jun 11];400(10353):680–90. Available from: https://pubmed.ncbi.nlm.nih.gov/36007534/ Luukinen H, Koski K, Laippala P, Kivelä SL (1995) Predictors for recurrent falls among the home-dwelling elderly. Scand J Prim Health Care [Internet]. [cited 2025 Jun 11];13(4):294–9. Available from: https://pubmed.ncbi.nlm.nih.gov/8693215/ Tromp AM, Smit JH, Deeg DJH, Bouter LM, Lips P (1998) Predictors for falls and fractures in the longitudinal aging study Amsterdam. Journal of Bone and Mineral Research [Internet]. [cited 2025 Jun 11];13(12):1932–9. Available from: https://pubmed.ncbi.nlm.nih.gov/9844112/ Kelly KD, Pickett W, Yiannakoulas N, Rowe BH, Schopflocher DP, Svenson L et al Medication use and falls in community-dwelling older persons. Age Ageing [Internet]. 2003 Sep [cited 2025 Jun 11];32(5):503–9. Available from: https://pubmed.ncbi.nlm.nih.gov/12957999/ Mayo NE, Korner-Bitensky N, Becker R, Georges P (1989) Predicting falls among patients in a rehabilitation hospital. Am J Phys Med Rehabil [Internet]. [cited 2025 Jun 11];68(3):139–46. Available from: https://pubmed.ncbi.nlm.nih.gov/2730782/ Titler MG, Shever LL, Kanak MF, Picone DM, Qin R (2011) Factors associated with falls during hospitalization in an older adult population. Res Theory Nurs Pract [Internet]. [cited 2025 Jun 11];25(2):127–48. Available from: https://pubmed.ncbi.nlm.nih.gov/21696092/ Maximos M, Chang F, Patel T Risk of falls associated with antiepileptic drug use in ambulatory elderly populations: A systematic review. Canadian Pharmacists Journal: CPJ [Internet]. 2017 Mar 1 [cited 2025 Jun 12];150(2):101. Available from: https://pmc.ncbi.nlm.nih.gov/articles/PMC5384524/ Ishida JH, McCulloch CE, Steinman MA, Grimes BA, Johansen KL Gabapentin and Pregabalin Use and Association with Adverse Outcomes among Hemodialysis Patients. Journal of the American Society of Nephrology [Internet]. 2018 Jul 1 [cited 2025 Jun 12];29(7):1970–8. Available from: https://pubmed.ncbi.nlm.nih.gov/29871945/ Cai Y, Leveille S, Hausdorff J, Dong Z, Shi L, Manor B, IMPACT OF ANTICONVULSANT USE ON INCIDENCE OF FALLS IN OLDER PATIENTS WITH DIABETIC PERIPHERAL NEUROPATHY. Innov Aging [Internet]. 2018 Nov 1 [cited 2025 Jun 12];2(suppl_1):151–151. Available from: https://dx.doi.org/10.1093/geroni/igy023.547 Woolcott JC, Richardson KJ, Wiens MO, Patel B, Marin J, Khan KM et al (2009) Meta-analysis of the impact of 9 medication classes on falls in elderly persons. Arch Intern Med [Internet]. Nov 23 [cited 2025 Jun 11];169(21):1952–60. Available from: https://pubmed.ncbi.nlm.nih.gov/19933955/ de Vries M, Seppala LJ, Daams JG, van de Glind EMM, Masud T, van der Velde N et al Fall-Risk-Increasing Drugs: A Systematic Review and Meta-Analysis: I. Cardiovascular Drugs. J Am Med Dir Assoc [Internet]. 2018 Apr 1 [cited 2025 Jun 11];19(4):371.e1-371.e9. Available from: https://pubmed.ncbi.nlm.nih.gov/29396189/ Zaccara G, Gangemi P, Perucca P, Specchio L The adverse event profile of pregabalin: A systematic review and meta-analysis of randomized controlled trials. Epilepsia [Internet]. 2011 Apr [cited 2025 Jun 11];52(4):826–36. Available from: https://pubmed.ncbi.nlm.nih.gov/21320112/ Freynhagen R, Strojek K, Griesing T, Whalen E, Balkenohl M Efficacy of pregabalin in neuropathic pain evaluated in a 12-week, randomised, double-blind, multicentre, placebo-controlled trial of flexible- and fixed-dose regimens. Pain [Internet]. 2005 Jun [cited 2025 Jun 11];115(3):254–63. Available from: https://pubmed.ncbi.nlm.nih.gov/15911152/ Additional Declarations The authors declare no competing interests. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6945897","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Systematic Review","associatedPublications":[],"authors":[{"id":474504489,"identity":"4b7dfd90-473c-46ca-9168-03cab86c66c0","order_by":0,"name":"Arun 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chart\u003c/p\u003e","description":"","filename":"image1.png","url":"https://assets-eu.researchsquare.com/files/rs-6945897/v1/68a62c241a089727a2fceca5.png"},{"id":85369033,"identity":"61db6ca9-21f5-48ae-9e02-f8b22ab52972","added_by":"auto","created_at":"2025-06-25 07:14:58","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":489281,"visible":true,"origin":"","legend":"\u003cp\u003eTraffic Light Plots on RoB of included RCTs\u003c/p\u003e","description":"","filename":"image2.png","url":"https://assets-eu.researchsquare.com/files/rs-6945897/v1/0e78e6bccdccd04e7d6de026.png"},{"id":85369032,"identity":"99c69a47-a3b8-4754-a9de-0230054556a1","added_by":"auto","created_at":"2025-06-25 07:14:58","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":1728782,"visible":true,"origin":"","legend":"\u003cp\u003eTraffic Light plots on the RoB assessment on included non-RCT studies\u003c/p\u003e","description":"","filename":"image3.png","url":"https://assets-eu.researchsquare.com/files/rs-6945897/v1/ffafa75a569a8da8feccb063.png"},{"id":85371904,"identity":"c7191bb8-d15b-48d2-b93c-c1ae011968cf","added_by":"auto","created_at":"2025-06-25 07:39:02","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":86391,"visible":true,"origin":"","legend":"\u003cp\u003eForest plot showing pooled incidence of falls in older adults treated with AEDs\u003c/p\u003e","description":"","filename":"image4.png","url":"https://assets-eu.researchsquare.com/files/rs-6945897/v1/0b5c961d65d75a99210f15b0.png"},{"id":85369738,"identity":"ae346e20-f169-4d57-831f-2f80042fda40","added_by":"auto","created_at":"2025-06-25 07:22:58","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":163667,"visible":true,"origin":"","legend":"\u003cp\u003eForest plot showing incidence of dizziness associated with AED use in older adults\u003c/p\u003e","description":"","filename":"image5.png","url":"https://assets-eu.researchsquare.com/files/rs-6945897/v1/00adee845922a781e019612d.png"},{"id":85369735,"identity":"93ac1c02-cf5e-405d-808d-7533f3e45baa","added_by":"auto","created_at":"2025-06-25 07:22:58","extension":"png","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":145093,"visible":true,"origin":"","legend":"\u003cp\u003eForest plot showing incidence of somnolence (drowsiness) with AED use in older adults\u003c/p\u003e","description":"","filename":"image6.png","url":"https://assets-eu.researchsquare.com/files/rs-6945897/v1/7395bdbeaf05f984e386e87e.png"},{"id":85369035,"identity":"f8de3efb-ae74-4467-8f78-5e2e6e2cd5b0","added_by":"auto","created_at":"2025-06-25 07:14:58","extension":"png","order_by":7,"title":"Figure 7","display":"","copyAsset":false,"role":"figure","size":89555,"visible":true,"origin":"","legend":"\u003cp\u003eForest plot of sedation incidence linked to AEDs in older adults\u003c/p\u003e","description":"","filename":"image7.png","url":"https://assets-eu.researchsquare.com/files/rs-6945897/v1/911dd08742a1440758e51d4e.png"},{"id":85369741,"identity":"7d16fcea-1656-4c73-bde5-8538d3472f18","added_by":"auto","created_at":"2025-06-25 07:22:58","extension":"png","order_by":8,"title":"Figure 8","display":"","copyAsset":false,"role":"figure","size":112002,"visible":true,"origin":"","legend":"\u003cp\u003eForest plot showing incidence of vertigo following AED treatment in older populations\u003c/p\u003e","description":"","filename":"image8.png","url":"https://assets-eu.researchsquare.com/files/rs-6945897/v1/fd2c45922803f4bc9eea00f0.png"},{"id":85370938,"identity":"07fc83f5-8656-4e8a-b9fc-2a498560fdbf","added_by":"auto","created_at":"2025-06-25 07:30:58","extension":"png","order_by":9,"title":"Figure 9","display":"","copyAsset":false,"role":"figure","size":83100,"visible":true,"origin":"","legend":"\u003cp\u003eForest plot summarising ataxia incidence across included studies of AEDs in older adults\u003c/p\u003e","description":"","filename":"image9.png","url":"https://assets-eu.researchsquare.com/files/rs-6945897/v1/f12203e749efe075806631fc.png"},{"id":85371925,"identity":"48ef50a6-871e-42e5-80f5-2496c5833c2e","added_by":"auto","created_at":"2025-06-25 07:39:12","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":3314128,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6945897/v1/ed7ffb83-70e7-4c80-9166-49c304463340.pdf"}],"financialInterests":"The authors declare no competing interests.","formattedTitle":"\u003cp\u003e\u003cstrong\u003eFall-Related Adverse Events of Anti-Epileptic Drugs used for Neuropathic Pain in Older Adults: A systematic Review and Meta-Analysis\u003c/strong\u003e\u003c/p\u003e","fulltext":[{"header":"Key Points","content":"\u003cul\u003e\n \u003cli\u003eAntiepileptic drugs such as gabapentin, and pregabalin are commonly prescribed for neuropathic pain in older adults, but their safety profiles in this population are not well established.\u003c/li\u003e\n \u003cli\u003eThis systematic review and meta-analysis synthesised data from 23 studies and found consistent associations between specific antiepileptic drugs and fall-related adverse events, including dizziness, sedation, and impaired coordination.\u003c/li\u003e\n \u003cli\u003eGabapentin was associated with a comparatively lower risk of fall-related adverse events, suggesting it may be a safer option among antiepileptic drugs for older adults when used for neuropathic pain.\u003c/li\u003e\n \u003cli\u003eThe risk of these adverse outcomes varied across individual antiepileptic drugs, suggesting a need for drug-specific risk-benefit assessments in older patients. These findings support more cautious, individualised prescribing in older people with neuropathic pain, alongside routine fall-risk monitoring to improve medication safety.\u003c/li\u003e\n\u003c/ul\u003e"},{"header":"1. Introduction","content":"\u003cp\u003eNeuropathic pain is a common and disabling condition among older adults, with prevalence rates ranging from 7\u0026ndash;10% in community-dwelling populations and even higher among institutionalized older Adults individuals (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e). Initial treatments for neuropathic pain frequently include antiepileptic drugs (AEDs) such as gabapentin, pregabalin, and carbamazepine, which act by modulating calcium channels and sodium conductance in nociceptive pathways (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e). However, these medications also exert significant central nervous system (CNS) effects, resulting in common adverse events such as dizziness, sedation, ataxia, and somnolence\u0026mdash;factors strongly associated with increased fall risk in older adults (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eFalls are the leading cause of injury, hospitalization, and loss of independence in people aged\u0026thinsp;\u0026ge;\u0026thinsp;65, with roughly 30% of older adults experiencing at least one fall annually(\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e). Importantly, medications are among the most modifiable risk factors for falls, and polypharmacy involving CNS-active drugs such as AEDs and antidepressants is particularly hazardous (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e). Despite this, older adults are frequently underrepresented or excluded from randomized controlled trials (RCTs), especially in dose-finding studies, resulting in an evidence gap regarding drug safety in real-world geriatric populations (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eAlthough observational studies have linked AEDs to increased fall risk, with odds ratios as high as 2.55 (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e), these studies often lack dosage stratification and are susceptible to confounding. A recent review by Zia et al. (2017)(\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e) emphasized the urgent need for high-quality studies that delineate drug-specific and dose-dependent risks in older populations. In the absence of such data, clinicians face significant uncertainty in balancing analgesic efficacy with fall-related harms(\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e). Most existing literature either aggregates data across diverse CNS-active drug classes or fails to stratify by age and dose, limiting clinical applicability(\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e). This lack of granular evidence leaves prescribers without robust guidance on which AEDs may pose higher risks at certain doses in geriatric populations(\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThis study aims to address critical knowledge gaps by systematically evaluating and quantifying the incidence of fall-related adverse events in older adults receiving AEDs for neuropathic pain. Given the heightened vulnerability of older populations to falls\u0026mdash;often triggered by CNS-active medications\u0026mdash;this analysis focuses specifically on identifying drug- and dose-dependent risk patterns. Using data from randomized controlled trials and controlled observational studies, the review quantifies the incidence of key fall-associated adverse events, including dizziness, somnolence, sedation, vertigo, and ataxia. Importantly, it not only examines aggregate risk but also stratifies by individual AEDs and their corresponding dosages to determine differential safety profiles. By doing so, the study seeks to inform safer prescribing practices, especially in geriatric care settings where polypharmacy and comorbidities complicate treatment decisions. The findings are intended to support clinicians in balancing analgesic efficacy with fall risk, ultimately guiding more individualized and risk-aware pharmacologic management of neuropathic pain in older adults.\u003c/p\u003e"},{"header":"2. Methods","content":"\u003cp\u003eThis study was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines (\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e) for conducting systematic reviews and meta-analyses. Compliance with the principles of the Declaration of Helsinki further reinforced the ethical foundation of this review. This review exclusively analyzed secondary data from existing studies and, therefore, qualifies for exemption from informed consent or institutional review board approval. The study protocol was registered on the PROSPERO online database with the registration number CRD420251048827\u003c/p\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003e2.1 Search Strategy:\u003c/h2\u003e \u003cp\u003eA comprehensive and systematic literature search was conducted by two authors (AV and VV) across five electronic databases PubMed, Cochrane Library, Scopus, ScienceDirect and CINAHL covering studies published up to May 2025 as described in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. The search strategy was developed using a combination of MeSH terms and free-text keywords related to AED (e.g., \u0026ldquo;gabapentin,\u0026rdquo; \u0026ldquo;pregabalin,\u0026rdquo; \u0026ldquo;carbamazepine,\u0026rdquo; \u0026ldquo;lamotrigine\u0026rdquo;), adverse events (e.g., \u0026ldquo;falls,\u0026rdquo; \u0026ldquo;dizziness,\u0026rdquo; \u0026ldquo;ataxia,\u0026rdquo; \u0026ldquo;somnolence,\u0026rdquo; \u0026ldquo;sedation,\u0026rdquo; \u0026ldquo;vertigo\u0026rdquo;), and older populations (e.g., \u0026ldquo;elderly,\u0026rdquo; \u0026ldquo;aged,\u0026rdquo; \u0026ldquo;older adults\u0026rdquo;). Boolean operators (AND/OR) were used to structure search strings, with database-specific syntax adjustments. Filters were applied to restrict results to human studies involving participants aged\u0026thinsp;\u0026ge;\u0026thinsp;60 years. Only English-language publications were included. Duplicates were removed using automated reference management tools, followed by manual screening. Records lacking free full-text availability were excluded. Titles and abstracts were screened for relevance, and full-texts were assessed against predefined inclusion criteria. Reference lists of included studies were also manually searched to identify additional eligible studies.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eDetailed database search strategy with keywords and Boolean operators used across MEDLINE, Embase, and CENTRAL\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"2\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDatabase\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSearch Strategy String\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eScopus\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e( \"antiepileptic drugs\" AND elderly )\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCINAHL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e(\"antiepileptic drugs\" OR AEDs OR gabapentin OR pregabalin OR carbamazepine OR lamotrigine OR oxcarbazepine OR lacosamide) AND (\"older adults\" OR elderly OR aged) AND (falls OR \"fall risk\" OR dizziness OR vertigo OR ataxia OR somnolence OR sedation) AND (\"randomized controlled trial\" OR clinical trial)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eScienceDirect\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\"antiepileptic\" AND \"falls\" AND \"older adults\"\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePubMed\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e(\"gabapentin\"[Supplementary Concept] OR \"gabapentin\"[All Fields] OR \"gabapentin\"[MeSH Terms] OR \"gabapentine\"[All Fields] OR \"gabapentin s\"[All Fields] OR (\"pregabalin\"[Supplementary Concept] OR \"pregabalin\"[All Fields] OR \"pregabalin\"[MeSH Terms] OR \"pregabalin s\"[All Fields] OR \"pregabaline\"[All Fields]) OR (\"carbamazepine\"[Supplementary Concept] OR \"carbamazepine\"[All Fields] OR \"carbamazepin\"[All Fields] OR \"carbamazepine\"[MeSH Terms] OR \"carbamazepines\"[All Fields] OR \"carbamazepine s\"[All Fields]) OR (\"lamotrigin\"[All Fields] OR \"lamotrigine\"[Supplementary Concept] OR \"lamotrigine\"[All Fields] OR \"lamotrigine\"[MeSH Terms] OR \"lamotrigine s\"[All Fields]) OR (\"oxcarbazepin\"[All Fields] OR \"oxcarbazepine\"[Supplementary Concept] OR \"oxcarbazepine\"[All Fields] OR \"oxcarbazepine\"[MeSH Terms]) OR (\"lacosamide\"[Supplementary Concept] OR \"lacosamide\"[All Fields] OR \"lacosamide\"[MeSH Terms])) AND (\"accidental falls\"[MeSH Terms] OR (\"accidental\"[All Fields] AND \"falls\"[All Fields]) OR \"accidental falls\"[All Fields] OR \"falling\"[All Fields] OR \"falls\"[All Fields] OR \"fallings\"[All Fields] OR (\"dizziness\"[MeSH Terms] OR \"dizziness\"[All Fields] OR \"dizzy\"[All Fields] OR \"vertigo\"[MeSH Terms] OR \"vertigo\"[All Fields]) OR (\"ataxia\"[MeSH Terms] OR \"ataxia\"[All Fields] OR \"ataxias\"[All Fields]) OR (\"vertigo\"[MeSH Terms] OR \"vertigo\"[All Fields] OR \"vertigos\"[All Fields] OR \"vertigoes\"[All Fields]) OR (\"sleepiness\"[MeSH Terms] OR \"sleepiness\"[All Fields] OR \"somnolence\"[All Fields] OR \"somnolent\"[All Fields]) OR (\"sedate\"[All Fields] OR \"sedated\"[All Fields] OR \"sedating\"[All Fields] OR \"sedation\"[All Fields] OR \"sedations\"[All Fields]))\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCochrane Library\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e(\"antiepileptic drugs\" OR gabapentin OR pregabalin OR carbamazepine OR lamotrigine OR oxcarbazepine OR lacosamide) AND (\"older adults\" OR elderly OR aged) AND (\"neuropathic pain\") AND (falls OR dizziness OR ataxia OR vertigo OR somnolence OR sedation) IN Trials\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003e2.2 Study selection:\u003c/h2\u003e \u003cp\u003eStudy selection was performed using the PICOS (Participants, Intervention, Comparisons, Outcomes, and Study Design) framework to define inclusion and exclusion criteria. The inclusion and exclusion criteria for this systematic review were defined using the PICOS framework to ensure methodological rigor and relevance to the research objectives. Population criteria included studies involving older adults aged\u0026thinsp;\u0026gt;\u0026thinsp;50 years, reflecting the population most vulnerable to antiepileptic drug (AED)-associated adverse events (AEs) such as falls. Interventions were restricted to AEDs prescribed for neuropathic pain, including gabapentin, pregabalin, carbamazepine, oxcarbazepine, lamotrigine, lacosamide, levetiracetam, and related agents. Comparators included placebo, usual care, or other AEDs, allowing for assessment of relative safety profiles. Outcomes required clear reporting of fall-related AEs including falls, dizziness, ataxia, vertigo, somnolence, or sedation. Study design inclusion was limited to randomized controlled trials (RCTs), cohort studies, and controlled observational studies that provided extractable quantitative data. Studies were excluded if they did not report on older populations or failed to stratify data by age, focused on other indications such as epilepsy without mention of the adverse events relating to fall, assessed non-AED interventions, did not report on falls or neuropsychiatric AEs relevant to fall risk, or were reviews, editorials, letters, case reports, or non-English publications. These criteria ensured that the selected studies were both clinically relevant and methodologically sound for evaluating the risk of falls related to AEDs in the older adults.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003e2.3 Data Collection and Quality Evaluation:\u003c/h2\u003e \u003cp\u003eData collection and quality evaluation were carried out independently by two reviewers, who screened the titles and abstracts of studies in Mendeley Cite based on the inclusion criteria. Full texts of potentially eligible studies were reviewed, with disagreements resolved through decisioning by a blinded third author (NY). Data were extracted into a pre-tested Microsoft Excel sheet for consistency, documenting key details such as author, year, study design, country, diagnosis, sample size, mean age, interventions and measured outcomes. Methodological rigor and potential biases were also documented to ensure systematic data collection and analysis. The methodological quality of the included studies was rigorously evaluated using established tools tailored to study design. For randomized controlled trials (RCTs), the Revised Cochrane Risk of Bias tool (RoB 2)(\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e) was applied to assess bias across domains such as randomization, deviations from intended interventions, missing outcome data, measurement of outcomes, and selection of reported results. Non-randomized studies were assessed using the ROBINS-I (Risk Of Bias In Non-randomised Studies - of Interventions)(\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e) tool, which evaluates confounding, selection bias, classification of interventions, deviations, missing data, measurement of outcomes, and reporting bias. Each study was independently appraised by two reviewers, with discrepancies resolved through consensus. Additionally, the overall certainty of the evidence for each outcome was graded using the GRADE (Grading of Recommendations, Assessment, Development, and Evaluations)(\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e) framework, which considers study limitations, inconsistency, indirectness, imprecision, and publication bias. This comprehensive evaluation ensured the reliability and interpretability of the synthesized evidence.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003e2.4 Statistical Analysis:\u003c/h2\u003e \u003cp\u003eThe statistical analysis for this meta-analysis was conducted using Comprehensive Meta-Analysis (CMA) software version 3.7. Pooled estimates of logit event rates and corresponding standard errors were calculated using a fixed-effects model, appropriate due to the generally low heterogeneity observed across studies. The primary measure of effect was the logit event rate, which allowed for consistent transformation of event proportions across studies, particularly when event rates were near 0 or 1. Standard errors and 95% confidence intervals were calculated for each logit event rate. Subgroup analyses were conducted based on drug type and dose to evaluate variation in adverse events such as falls, dizziness, somnolence, sedation, vertigo, and ataxia among older patients treated with AED. A Z-test determined the statistical significance of pooled outcomes, with p\u0026thinsp;\u0026lt;\u0026thinsp;0.05 considered significant. Heterogeneity among studies was quantified using the Q statistic, p-value, and I\u0026sup2; index, with I\u0026sup2; values below 30% considered low. Publication bias was assessed through both Begg\u0026rsquo;s rank correlation test and Egger\u0026rsquo;s regression intercept test. In cases where asymmetry was detected in funnel plots, potential bias was further explored through sensitivity analyses. This rigorous approach ensured a statistically robust synthesis of evidence, supporting reliable conclusions for clinical application.\u003c/p\u003e \u003c/div\u003e"},{"header":"3. Results","content":"\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003e3.1 Study Selection:\u003c/h2\u003e \u003cp\u003eThe PRISMA flowchart illustrates the systematic process of literature identification, screening, and selection applied in this study. A total of 4,447 records were initially retrieved from five electronic databases: PubMed (n\u0026thinsp;=\u0026thinsp;2,326), Cochrane Library (n\u0026thinsp;=\u0026thinsp;137), Scopus (n\u0026thinsp;=\u0026thinsp;1,018), ScienceDirect (n\u0026thinsp;=\u0026thinsp;898), and CINAHL (n\u0026thinsp;=\u0026thinsp;68). Following the removal of duplicates (n\u0026thinsp;=\u0026thinsp;2,407) and records lacking free full-text access (n\u0026thinsp;=\u0026thinsp;253), 1,787 records were screened. An automated exclusion tool removed 873 records based on title and abstract relevance. The remaining 914 records were sought for full-text retrieval, but 542 could not be accessed or retrieved, leaving 372 reports for full eligibility assessment. Among these, 286 were excluded for not specifically addressing older adult populations, 33 due to unrelated interventions, and 30 for lacking data on falls or related adverse events. Ultimately, 23 studies met the inclusion criteria and were incorporated into the final review.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003e3.2 Study Characteristics:\u003c/h2\u003e \u003cp\u003eThe included studies encompass a diverse range of randomized controlled trials and observational designs evaluating the effects of antiepileptics and CNS-active medications on outcomes such as neuropathic pain, psychiatric symptoms, and fall risk in older adults. Sample sizes varied widely\u0026mdash;from as small as 8 participants (\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e) to over 41,000 subjects (\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e) with most studies focusing on older adults aged more than 50 years and above. Diagnoses addressed included chronic sciatica, painful diabetic neuropathy, epilepsy, bipolar depression, and dementia-related agitation. Interventions spanned a broad pharmacologic spectrum, including gabapentin, pregabalin, lamotrigine, carbamazepine, lacosamide, mirtazapine, and combinations with B vitamins or antidepressants. Several studies employed head-to-head comparisons or combination therapy strategies. Common findings included gabapentin\u0026rsquo;s superior tolerability over pregabalin (\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e), and a consistent association between CNS drugs and increased fall risk across multiple cohort studies (\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e). Despite methodological variability, the studies collectively support the clinical relevance of medication-induced adverse effects, especially in geriatric populations, and underscore the importance of individualized, risk-balanced pharmacologic management.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eCharacteristics of included studies evaluating AED-related fall risk in older adults\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"7\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eStudy\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCountry\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eSample Size\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMean Age\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eDiagnosis\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eInterventions\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003eKey Findings\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRobertson et al, 2018 (\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAustralia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e18\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e57\u0026thinsp;\u0026plusmn;\u0026thinsp;16.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eChronic Sciatica\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eGabapentin vs Pregabalin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eGabapentin superior in pain reduction and fewer adverse events compared to pregabalin.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRichards et al, 2025(\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eUSA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e147\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e83.4\u0026thinsp;\u0026plusmn;\u0026thinsp;9.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eRLS with dementia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eGabapentin enacarbil vs Placebo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eReduced nighttime agitation; trend toward more falls in the gabapentin group (P\u0026thinsp;=\u0026thinsp;0.066).\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSaetre et al, 2009(\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNorway\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e108\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026ge;\u0026thinsp;65\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eNewly diagnosed epilepsy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eCarbamazepine vs Lamotrigine\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eNo significant ECG changes; both drugs tolerated well in older Adults.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBrodie et al, 1999(\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eUK/Europe\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e150\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e77\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eNewly diagnosed epilepsy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eLamotrigine vs Carbamazepine\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eLamotrigine had fewer adverse events and better continuation than carbamazepine.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSajatovic et al, 2011(\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eUSA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e57\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e66.5\u0026thinsp;\u0026plusmn;\u0026thinsp;6.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eBipolar depression\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eLamotrigine (augmentation)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eImprovement in depression and function; some adverse events including unsteady gait.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRoose et al, 2003(\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eUSA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e119\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026ge;\u0026thinsp;70\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eDepression\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eMirtazapine (15\u0026ndash;45 mg/day)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eEffective in depression; common AEs were falls (18%) and somnolence (12%).\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAlvarado et al, 2016(\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMexico\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e270\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;50\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003ePainful diabetic neuropathy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eGabapentin\u0026thinsp;+\u0026thinsp;B1/B12 vs Pregabalin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eComparable efficacy; less vertigo with gabapentin/B1/B12 (P\u0026thinsp;=\u0026thinsp;0.014); lower gabapentin doses needed for pain relief.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSaetre et al 2007(\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNorway/Multicenter\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e185\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026ge;\u0026thinsp;65\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eNewly diagnosed epilepsy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eLamotrigine (25\u0026ndash;500 mg/day), Carbamazepine SR (100\u0026ndash;2000 mg/day)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eLTG and CBZ had similar effectiveness; CBZ had higher seizure freedom, LTG better tolerability.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFreynhagen et al 2005(\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMulticenter\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e338\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e62.7\u0026thinsp;\u0026plusmn;\u0026thinsp;10.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eDPN or PHN (neuropathic pain)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003ePregabalin (flexible: 150\u0026ndash;600 mg/day or fixed: 300\u0026ndash;600 mg/day)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eBoth regimens reduced pain and sleep interference; dizziness and somnolence common AEs.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDworkin et al 2009(\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eUSA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e87\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026ge;\u0026thinsp;50\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eAcute pain in herpes zoster\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eGabapentin (1200\u0026ndash;1800 mg/day), CR-oxycodone, placebo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eOxycodone reduced pain more than placebo; gabapentin had modest effect; common AEs included constipation.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eJensen-Dahm et al 2011(\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eUSA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e65\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eAcute herpes zoster pain\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003ePregabalin (150 mg single dose)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e33% pain reduction vs 14% placebo; well tolerated; effects on allodynia not significant.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHolbech et al (2015)(\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMulticenter (EU)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e73\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e20\u0026ndash;85 years\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003ePainful polyneuropathy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eImipramine 75 mg/day vs Pregabalin 300 mg/day vs Combination vs Placebo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eCombination significantly more effective than either monotherapy but had more adverse events.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSommer et al (2009)(\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eGermany\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e103\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e83\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eAgitation/aggression in dementia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eOxcarbazepine vs Placebo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eNo significant difference in agitation/aggression; slight trend favoring oxcarbazepine.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWymer et al (2009)(\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eInternational\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e58\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003ePainful diabetic neuropathy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eLacosamide 200 mg/d, 400 mg/d, 600 mg/d vs Placebo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eLacosamide 400 mg/d showed optimal efficacy/tolerability; 600 mg/d had high AE dropout rate.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTesfaye et al (2022)(\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eUK (13 sites)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e130\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMean: 60s\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eDiabetic peripheral neuropathic pain (DPNP)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eA-P, P-A, D-P pathways combining amitriptyline, duloxetine, pregabalin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eAll had similar efficacy; combination better than monotherapy if pain relief suboptimal.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDustin et al, 2006(\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eUSA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e41,102 (20,551 cases, 20,551 controls)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;65\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eFall-related outpatient visits vs nonspecific chest pain\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eAnalysis of CNS, CVS, and MSS drugs prescribed\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eCNS drugs (e.g., antidepressants, anticonvulsants, antipsychotics) more common in fall patients. CVS drugs more common in controls. Highlighted medication-related fall risk.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLuukinen et al, 1995(\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eFinland\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1016\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026ge;\u0026thinsp;70\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eRecurrent falls in home-dwelling older Adults\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eCommunity-based observation and fall history\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003ePrior falls, peripheral neuropathy, psychotropics, and slow gait identified as predictors of recurrent falls.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTromp et al, 1998(\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNetherlands\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1469\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;60 (Born before 1931)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eFalls, recurrent falls, fractures\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003ePopulation-based cohort analysis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eImpaired mobility, analgesics, and antiepileptics predicted recurrent falls. Fractures predicted by inactivity, female gender, and prior fractures.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eKelly et al, 2003(\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNetherlands\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1469\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;60\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eRecurrent falls and fractures\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eBaseline interview with follow-up over 38 months\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eSimilar to Tromp et al: identified analgesics and inactivity as strong predictors. Recurrent falls occurred in 15% of the cohort.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMayo et al, 1989(\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCanada\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e402 (201 cases, 201 controls)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;60\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eFalls in rehabilitation hospital\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eRetrospective case-control from admission records\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eStroke, incontinence, anticonvulsants, and topical eye meds predicted falls. Risk model validated in second cohort year.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEnsrud et al. 2002(\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eUSA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e8,127 women\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026ge;\u0026thinsp;65 years\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eCommunity-dwelling older women\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eCNS-active drugs: benzodiazepines, antidepressants, anticonvulsants, narcotics\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eUse of benzodiazepines (OR: 1.51), antidepressants (OR: 1.54), and anticonvulsants (OR: 2.56) significantly increased risk of frequent falls. Narcotics not associated.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMasud et al. 2013(\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eDenmark\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4,696 men\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMedian: 66.3 years\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eMen aged 60\u0026ndash;75 years, general population\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eCNS drugs: opiates, antidepressants, anxiolytics, SSRIs, TCAs\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eOpiates (OR: 2.4), antidepressants (OR: 2.8), SSRIs (OR: 3.1), TCAs (OR: 2.2), and antiepileptics (OR: 2.8) significantly associated with falls.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTitler et al. 2011(\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eUSA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e10,187 hospitalizations\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026ge;\u0026thinsp;60 years\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eHospitalized older adults\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eMedical/pharmacy/nursing treatments; CNS meds; fall prevention interventions\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eAntidepressants, antipsychotics, benzodiazepines, restraints, and neurologic monitoring linked to falls. RN skill mix, ulcer care, and pain management inversely related.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003e3.3 Risk of Bias Assessment:\u003c/h2\u003e \u003cp\u003eThe risk of bias for the 15 randomized controlled trials (RCTs) included in this analysis was evaluated using the RoB 2 tool. Most RCTs demonstrated a low overall risk of bias, particularly in domains related to randomization, adherence to intended interventions, and outcome measurement. Studies by Robertson et al. (2018)(\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e), Saetre et al. (2007, 2009)(\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e), and Tesfaye et al. (2022)(\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e) were rigorously designed with appropriate allocation concealment, blinding, and complete outcome reporting. A few studies, such as Sajatovic et al. (2011)(\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e) and Wymer et al. (2009)(\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e), showed \u0026ldquo;some concerns\u0026rdquo; due to moderate dropout rates or adverse event-related attrition, potentially influencing outcome reliability. Holbech et al. (2015) also raised concern due to higher dropout in the combination arm. Despite these limitations, most studies maintained methodological robustness, ensuring reliable efficacy and safety comparisons of antiepileptic and CNS-active medications in older adults.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eFor the eight observational studies and cohort designs, the ROBINS-I tool was applied to assess bias. Most prospective cohort studies, including those by Luukinen et al. (1995)(\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e), Tromp et al. (1998)(\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e), and Ensrud et al. (2002)(\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e), were deemed low risk across domains due to well-defined participant selection, standardized outcome assessment, and control of key confounders. Conversely, retrospective studies such as Dustin et al. (2006)(\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e) and Mayo et al. (1989)(\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e) were rated as having moderate bias due to limitations in confounder adjustment, potential selection bias, and missing data handling. Cross-sectional data from Masud et al. (2013)(\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e) and retrospective registry-based data in Titler et al. (2011)(\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e) also indicated moderate bias due to measurement and reporting variability. These findings underscore the need for cautious interpretation of results from non-randomized studies, although they provide valuable real-world insights into fall risk associations with CNS medication use in the older Adults.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003e3.4 GRADE assessment:\u003c/h2\u003e \u003cp\u003eThe GRADE assessment of included studies revealed a moderate to high certainty of evidence for most randomized controlled trials (RCTs), particularly those evaluating antiepileptic and neuropathic pain medications in older populations. Studies such as Saetre et al. (2007), Freynhagen et al. (2005)(\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e), and Tesfaye et al. (2022)(\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e) demonstrated high methodological rigor, consistent results, and direct clinical applicability, thereby achieving a high certainty rating. Conversely, trials with small sample sizes, high dropout rates, or imprecision in outcome estimates\u0026mdash;such as those by Jensen-Dahm et al. (2011)(\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e) and Roose et al. (2003)(\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e)\u0026mdash;were downgraded to low or moderate certainty. Among observational studies, the certainty of evidence was generally moderate, as seen in large-scale cohort studies like Ensrud et al. (2002)(\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e) and Masud et al. (2013)(\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e), which provided robust associations between CNS-active drugs and fall risk. However, studies such as Mayo et al. (1989)(\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e) and Titler et al. (2011)(\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e) were rated low due to potential confounding and imprecision. Overall, the GRADE findings reinforce the reliability of key conclusions while also highlighting areas requiring cautious interpretation due to methodological limitations.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eGRADE quality assessment of evidence for adverse event outcomes in older adults using antiepileptic drugs\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"8\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eStudy\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eOutcome\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eRisk of Bias\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eInconsistency\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eIndirectness\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eImprecision\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003ePublication Bias\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c8\"\u003e \u003cp\u003eCertainty of Evidence\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRobertson et al., 2018\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePain reduction\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eLow\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eLow\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eLow\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eSerious (small sample)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eLow\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eModerate\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRichards et al., 2025\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAgitation reduction\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eLow\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eLow\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eLow\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eSerious (high AE rate)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eLow\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eModerate\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSaetre et al., 2009\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eECG safety\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eLow\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eLow\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eLow\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eLow\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eLow\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eHigh\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBrodie et al., 1999\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAED tolerability\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eSome concerns\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eLow\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eLow\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eSerious (older trial)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eLow\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eModerate\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSajatovic et al., 2011\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eDepression response\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eSome concerns\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eModerate\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eLow\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eSerious\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eLow\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eLow\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRoose et al., 2003\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eDepression symptoms\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eSome concerns\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eModerate\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eSerious\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eSerious\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eLow\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eLow\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAlvarado et al., 2016\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNeuropathic pain\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eLow\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eLow\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eLow\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eLow\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eLow\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eHigh\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSaetre et al., 2007\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSeizure control\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eLow\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eLow\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eLow\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eLow\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eLow\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eHigh\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFreynhagen et al., 2005\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eDPN/PHN pain\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eLow\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eLow\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eLow\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eLow\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eLow\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eHigh\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDworkin et al., 2009\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAcute zoster pain\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eLow\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eLow\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eLow\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eSerious\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eLow\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eModerate\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eJensen-Dahm et al., 2011\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAcute zoster pain\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eLow\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eSerious (n\u0026thinsp;=\u0026thinsp;8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eLow\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eSerious\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eLow\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eLow\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHolbech et al., 2015\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePolyneuropathy pain\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eLow\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eLow\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eLow\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eSerious (dropouts)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eLow\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eModerate\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSommer et al., 2009\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAgitation\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eLow\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eLow\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eLow\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eSerious (underpowered)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eLow\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eModerate\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWymer et al., 2009\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eDPN pain\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eLow\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eLow\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eLow\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eLow\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eLow\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eHigh\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTesfaye et al., 2022\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eDPN pain\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eLow\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eLow\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eLow\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eLow\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eLow\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eHigh\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDustin et al., 2006\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eFalls vs drug class\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eModerate\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eLow\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eLow\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eLow\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eLow\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eLow\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLuukinen et al., 1995\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eRecurrent falls\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eLow\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eLow\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eLow\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eLow\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eLow\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eModerate\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTromp et al., 1998\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eRecurrent falls/fractures\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eLow\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eLow\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eLow\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eLow\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eLow\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eModerate\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMayo et al., 1989\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eHospital falls\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eModerate\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eLow\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eSerious\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eSerious\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eLow\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eLow\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEnsrud et al., 2002\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCNS meds \u0026amp; falls\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eLow\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eLow\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eLow\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eLow\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eLow\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eModerate\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMasud et al., 2013\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCNS meds in older men\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eLow\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eLow\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eLow\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eLow\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eLow\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eModerate\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTitler et al., 2011\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eHospital falls \u0026amp; interventions\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eModerate\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eLow\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eLow\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eSerious\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eLow\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eLow\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003e3.5 Incidence on Falls:\u003c/h2\u003e \u003cp\u003eThe Forest Plot in Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e evaluated the incidence of falls among older patients receiving AEDs for neuropathic pain, synthesizing data from eight studies and subgrouping by drug type. The overall pooled logit event rate was \u0026minus;\u0026thinsp;1.693 (SE\u0026thinsp;=\u0026thinsp;0.153; 95% CI: -1.993 to -1.393), which corresponds to an estimated fall incidence of approximately 15.5%. The heterogeneity across studies was low (Q\u0026thinsp;=\u0026thinsp;6.83; df\u0026thinsp;=\u0026thinsp;7; p\u0026thinsp;=\u0026thinsp;0.45; I\u0026sup2; = 0%), suggesting consistency in effect estimates. Among subgroups, Gabapentin was represented by three studies (\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e)(\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e), yielding a pooled logit of -2.20 (SE\u0026thinsp;=\u0026thinsp;0.32), equating to a lower fall incidence (~\u0026thinsp;10%) and moderate heterogeneity (I\u0026sup2; = 32.8%). Pregabalin, analyzed in two studies (\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e)(\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e) showed a higher logit rate of -1.53 (SE\u0026thinsp;=\u0026thinsp;0.68), suggesting\u0026thinsp;~\u0026thinsp;18% fall risk, with no significant heterogeneity (I\u0026sup2; = 0%). Lamotrigine (\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e), Mirtazapine (\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e), and Oxcarbazepine (\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e) were each evaluated in single studies, with logit event rates of -1.85, -1.52, and \u0026minus;\u0026thinsp;1.44 respectively, translating to a fall incidence ranging between 14% and 18%. The consistency in directionality across AEDs highlights a clinically meaningful risk of falls, particularly relevant in geriatric populations with neuropathic pain. Notably, gabapentin was associated with a comparatively lower risk, suggesting it may be a safer option in fall-prone older adults individuals. These findings emphasize the importance of fall-risk assessment and individualized drug selection in older adults, especially when initiating or titrating AED therapy for neuropathic pain. Further studies should explore dose-response relationships and mechanisms underlying differential fall risks across AEDs.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003e3.6 AE relating to Falls:\u003c/h2\u003e \u003cdiv id=\"Sec14\" class=\"Section3\"\u003e \u003ch2\u003e3.6.1 Incidence of Dizziness:\u003c/h2\u003e \u003cp\u003eThe Forest plot in Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003e revealed that dizziness is a prevalent adverse event (AE) among older patients prescribed AEDs for neuropathic pain, with an overall fixed-effect logit event rate of \u0026minus;\u0026thinsp;1.483 (SE\u0026thinsp;=\u0026thinsp;0.066), translating to an incidence of approximately 18.4%. The analysis demonstrated low heterogeneity (I\u0026sup2; = 22.3%), indicating consistency across studies. Drug-specific analysis showed that Lacosamide had the highest dizziness incidence (~\u0026thinsp;21.6%) with significant heterogeneity (I\u0026sup2; = 90.2%), reflecting dose-related variability between 200 mg and 600 mg regimens. Gabapentin (300\u0026ndash;3600 mg/day) also demonstrated a high incidence (~\u0026thinsp;19.7%) with moderate heterogeneity (I\u0026sup2; = 60.6%), likely due to wide dosing variations. In contrast, drugs like Lamotrigine (25\u0026ndash;500 mg/day) and Carbamazepine (300\u0026ndash;2000 mg/day) showed lower dizziness rates (~\u0026thinsp;16\u0026ndash;17%) and minimal heterogeneity (I\u0026sup2; = 0%), suggesting more stable safety profiles. Pregabalin (150\u0026ndash;600 mg/day) had a pooled incidence of ~\u0026thinsp;20.6% with consistent results across studies (I\u0026sup2; = 0%). Single-study estimates for Levetiracetam, Mirtazapine, and Oxcarbazepine showed dizziness incidences ranging from 13\u0026ndash;18%. The findings indicate a dose-dependent pattern, where higher or more rapidly titrated doses (notably for Gabapentin and Lacosamide) are associated with increased dizziness. Clinically, this underscores the importance of individualized dosing and cautious titration, especially in frail older adults at risk of falls. Agents like Lamotrigine and Carbamazepine may be preferable when aiming to minimize vestibular side effects. These results highlight the need for fall-prevention strategies and close monitoring of patients, particularly when initiating or up-titrating AED therapy in geriatric neuropathic pain management.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec15\" class=\"Section3\"\u003e \u003ch2\u003e3.6.2 Incidence of Somnolence:\u003c/h2\u003e \u003cp\u003eThis meta-analysis in Fig.\u0026nbsp;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e6\u003c/span\u003e examined the incidence of somnolence\u0026mdash;a critical adverse event (AE) linked to fall risk\u0026mdash;in older patients receiving AED for neuropathic pain. Thirteen studies were included, stratified by AED class and dosage. The overall pooled logit event rate was \u003cb\u003e\u0026minus;\u0026thinsp;1.667\u003c/b\u003e (SE\u0026thinsp;=\u0026thinsp;0.079), which corresponds to an approximate somnolence event rate of \u003cb\u003e15.9%\u003c/b\u003e. This indicates that somnolence is a clinically significant and relatively common AE in this population. The statistical association was robust (\u003cb\u003eZ = \u0026minus;\u0026thinsp;20.99, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001\u003c/b\u003e), and overall heterogeneity was low (\u003cb\u003eI\u0026sup2; = 16.7%, Q\u0026thinsp;=\u0026thinsp;14.41, df\u0026thinsp;=\u0026thinsp;12, p\u0026thinsp;=\u0026thinsp;0.275\u003c/b\u003e), suggesting consistent results across studies. Subgroup analysis by drug and dose showed notable trends. \u003cb\u003eCarbamazepine\u003c/b\u003e (300\u0026ndash;2000 mg) had a pooled logit of \u0026minus;\u0026thinsp;1.66 with mild heterogeneity (\u003cb\u003eI\u0026sup2; = 41.5%\u003c/b\u003e). \u003cb\u003eGabapentin\u003c/b\u003e (600\u0026ndash;3600 mg) and \u003cb\u003elamotrigine\u003c/b\u003e (75\u0026ndash;500 mg) had similar effects (logit ~\u0026ndash;1.55 to \u0026minus;\u0026thinsp;1.60) and negligible heterogeneity. \u003cb\u003ePregabalin\u003c/b\u003e (300\u0026ndash;600 mg) showed more variability (\u003cb\u003eI\u0026sup2; = 85.9%\u003c/b\u003e), possibly due to differing study designs and dose responses. Single-study data for \u003cb\u003elevetiracetam\u003c/b\u003e (3000 mg), \u003cb\u003eoxcarbazepine\u003c/b\u003e (2400 mg), and \u003cb\u003emirtazapine\u003c/b\u003e (15\u0026ndash;45 mg) also demonstrated strong associations with somnolence. These findings underscore the importance of careful AED selection and dose titration in the older adults, where even modest somnolence increases the risk of falls and associated morbidity. Clinicians should consider fall-prevention strategies and prefer agents with lower sedative burden. These results highlight the need for individualized risk\u0026ndash;benefit assessments, especially in frail older Patients with polypharmacy\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec16\" class=\"Section3\"\u003e \u003ch2\u003e3.6.3 Incidence of Sedation:\u003c/h2\u003e \u003cp\u003eThe meta-analysis in Fig.\u0026nbsp;\u003cspan refid=\"Fig7\" class=\"InternalRef\"\u003e7\u003c/span\u003e examined the incidence of sedation as an adverse event (AE)\u0026mdash;a key contributor to fall risk\u0026mdash;in older patients using AED (s) for neuropathic pain. The overall pooled logit event rate was \u0026minus;\u0026thinsp;1.700 (SE\u0026thinsp;=\u0026thinsp;0.158, p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001), translating to an estimated sedation rate of approximately 15.5%. The low heterogeneity (Q\u0026thinsp;=\u0026thinsp;7.60, df\u0026thinsp;=\u0026thinsp;7, p\u0026thinsp;=\u0026thinsp;0.37; I\u0026sup2; = 0%) suggests consistency across the eight included studies. Subgroup analysis by drug type and dosage revealed clinically relevant differences in sedation risk. For Gabapentin, sedation risk was observed across doses from 600 mg to 2400 mg, with the highest incidence noted at 1800 mg (logit event rate \u0026minus;\u0026thinsp;1.96, SE\u0026thinsp;=\u0026thinsp;0.57, p\u0026thinsp;=\u0026thinsp;0.0005, Dworkin et al.) and 1800 mg again in Mikkelsen et al. (logit \u0026minus;\u0026thinsp;1.81, SE\u0026thinsp;=\u0026thinsp;0.57, p\u0026thinsp;=\u0026thinsp;0.0013). At 600 mg (Richards et al. 2025), although the logit rate was \u0026minus;\u0026thinsp;1.64 (SE\u0026thinsp;=\u0026thinsp;0.32), statistical significance was higher (p\u0026thinsp;=\u0026thinsp;3.3\u0026times;10⁻⁷), indicating even lower doses warrant caution. For Pregabalin, the highest sedation incidence was seen at 600 mg in Tesfaye et al. 2022 (logit \u0026minus;\u0026thinsp;2.31, SE\u0026thinsp;=\u0026thinsp;0.34, p\u0026thinsp;=\u0026thinsp;7.4\u0026times;10⁻\u0026sup1;\u0026sup2;). Notably, 150 mg (Jensem-dahm 2011) showed a high logit rate (\u0026ndash;2.59) but with wide confidence intervals, likely due to small sample size. Oxcarbazepine, evaluated at 900 mg, also showed significant sedation (logit \u0026minus;\u0026thinsp;1.10, SE\u0026thinsp;=\u0026thinsp;0.32, p\u0026thinsp;=\u0026thinsp;0.0006). These findings underscore the need for careful dose selection and monitoring, especially at or above 600\u0026ndash;1800 mg for Gabapentin and 600 mg for Pregabalin. Clinicians must weigh analgesic benefit against sedation-induced fall risk in older patients, ensuring individualized therapy and fall-prevention strategies.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec17\" class=\"Section3\"\u003e \u003ch2\u003e3.6.4 Vertigo Incidence:\u003c/h2\u003e \u003cp\u003eThe Forest Plot in Fig.\u0026nbsp;\u003cspan refid=\"Fig8\" class=\"InternalRef\"\u003e8\u003c/span\u003e assessed the incidence of vertigo\u0026mdash;a key contributor to fall risk\u0026mdash;as an adverse event in older patients receiving AEDs for neuropathic pain. The overall pooled logit event rate was \u0026minus;\u0026thinsp;2.442 (SE\u0026thinsp;=\u0026thinsp;0.134, p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001), corresponding to an estimated vertigo incidence of approximately 8%. The analysis demonstrated no significant heterogeneity across the nine included studies (Q\u0026thinsp;=\u0026thinsp;4.62, df\u0026thinsp;=\u0026thinsp;8, p\u0026thinsp;=\u0026thinsp;0.80; I\u0026sup2; = 0%), suggesting consistent results across AED types and dosages. Carbamazepine at 2000 mg (Brodie et al., 1999) showed a logit event rate of \u0026minus;\u0026thinsp;2.11, translating to the highest vertigo incidence (\u0026asymp;\u0026thinsp;11.1%), with a strong statistical signal (p\u0026thinsp;=\u0026thinsp;3.6\u0026times;10⁻\u0026sup1;\u0026sup1;). For Gabapentin, the 3600 mg dose (Alvarado et al., 2016) had a notably high event rate (logit \u0026minus;\u0026thinsp;2.42; \u0026asymp;8.2%), whereas 2400 mg (Robertson et al., 2018) showed a lower and non-significant effect (p\u0026thinsp;=\u0026thinsp;0.08), suggesting a possible threshold for increased risk beyond 3000 mg. Lacosamide at both 600 mg and 200 mg (Wymer et al., 2009) had a combined logit of \u0026minus;\u0026thinsp;2.61 (\u0026asymp;\u0026thinsp;7.2%), showing a dose-independent consistent risk. Lamotrigine at 500 mg (Brodie et al., 1999) showed an event rate of approximately 10.5%. Among all, Pregabalin 600 mg (Alvarado et al., 2016) showed the lowest logit of \u0026minus;\u0026thinsp;3.18 (\u0026asymp;\u0026thinsp;4%), while the combined doses from three studies yielded a pooled rate of \u0026minus;\u0026thinsp;2.61 (\u0026asymp;\u0026thinsp;6.7%). Clinically, these findings suggest that higher doses of Carbamazepine (2000 mg), Gabapentin (\u0026ge;\u0026thinsp;3600 mg), and Lamotrigine (500 mg) are associated with higher vertigo incidence in older patients. Careful dose titration and vertigo monitoring are essential to minimize fall-related morbidity.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec18\" class=\"Section3\"\u003e \u003ch2\u003e3.6.5 Incidence of Ataxia:\u003c/h2\u003e \u003cp\u003eFigure \u003cspan refid=\"Fig9\" class=\"InternalRef\"\u003e9\u003c/span\u003e shows the results on meta-analysis, which evaluated the incidence of ataxia\u0026mdash;a critical adverse event (AE) contributing to fall risk\u0026mdash;in older patients treated with AEDs for neuropathic pain. The overall pooled logit event rate was \u0026minus;\u0026thinsp;1.875 (SE\u0026thinsp;=\u0026thinsp;0.170, p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001), which corresponds to an ataxia incidence of approximately 13.3% (using inverse logit transformation). This indicates a clinically meaningful rate of motor coordination impairment attributable to AED use in this population. Notably, heterogeneity was low and non-significant across the five included studies (Q\u0026thinsp;=\u0026thinsp;5.22, df\u0026thinsp;=\u0026thinsp;4, p\u0026thinsp;=\u0026thinsp;0.27; I\u0026sup2; = 23.4%), suggesting robust and consistent findings. Carbamazepine (2000 mg) showed a significant association with ataxia (logit \u0026minus;\u0026thinsp;1.61, p\u0026thinsp;=\u0026thinsp;1.38\u0026times;10⁻⁹), translating to an incidence of ~\u0026thinsp;17.8%. Similarly, Lamotrigine (500 mg) reported a logit of \u0026minus;\u0026thinsp;1.77 (p\u0026thinsp;=\u0026thinsp;1.54\u0026times;10⁻⁵; \u0026asymp;14.5% incidence), and Oxcarbazepine (900 mg) yielded a logit of \u0026minus;\u0026thinsp;1.71 (p\u0026thinsp;=\u0026thinsp;9.17\u0026times;10⁻⁶; \u0026asymp;15.3% incidence). Among Pregabalin doses, although both 300 mg and 600 mg were evaluated, the pooled logit rate was \u0026minus;\u0026thinsp;2.59 (p\u0026thinsp;=\u0026thinsp;4.83\u0026times;10⁻\u0026sup1;\u0026sup3;), corresponding to a lower incidence (~\u0026thinsp;7%), suggesting that Pregabalin may be better tolerated with respect to ataxia. Clinically, these findings underscore the need for careful dose selection and monitoring when prescribing AEDs to older adults. Higher doses of Carbamazepine, Lamotrigine, and Oxcarbazepine were associated with greater ataxia risk, which can significantly increase fall-related morbidity. Therefore, Pregabalin at moderate doses may be a safer alternative, although individualized risk\u0026ndash;benefit assessments remain crucial.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec19\" class=\"Section2\"\u003e \u003ch2\u003e3.7 Publication Bias:\u003c/h2\u003e \u003cp\u003ePublication bias across the outcomes falls, dizziness, somnolence, sedation, and vertigo was assessed using Begg and Mazumdar\u0026rsquo;s rank correlation test and Egger\u0026rsquo;s regression intercept and visually represented as Funnel plots in Supplementary Figs.\u0026nbsp;1\u0026ndash;6. For fall outcome, Kendall\u0026rsquo;s tau-b was \u0026minus;\u0026thinsp;0.321 (p\u0026thinsp;=\u0026thinsp;0.265), and Egger\u0026rsquo;s intercept was \u0026minus;\u0026thinsp;0.889 (95% CI: -2.79 to 1.01; p\u0026thinsp;=\u0026thinsp;0.296), suggesting no significant publication bias. Similarly, dizziness outcome assessment showed Kendall\u0026rsquo;s tau-b of -0.208 (p\u0026thinsp;=\u0026thinsp;0.176) and Egger\u0026rsquo;s intercept of -0.874 (95% CI: -2.14 to 0.39; p\u0026thinsp;=\u0026thinsp;0.164), again indicating no evidence of bias. For somnolence outcome, Begg\u0026rsquo;s tau-b was \u0026minus;\u0026thinsp;0.244 (p\u0026thinsp;=\u0026thinsp;0.246) and Egger\u0026rsquo;s intercept was \u0026minus;\u0026thinsp;1.474 (95% CI: -4.31 to 1.36; p\u0026thinsp;=\u0026thinsp;0.277), also non-significant. Sedation outcome demonstrated Kendall\u0026rsquo;s tau-b of -0.393 (p\u0026thinsp;=\u0026thinsp;0.174) and Egger\u0026rsquo;s intercept of -0.591 (95% CI: -3.02 to 1.83; p\u0026thinsp;=\u0026thinsp;0.573), with no bias indicated. Finally, vertigo outcome showed the strongest evidence against bias, with Kendall\u0026rsquo;s tau-b of -0.028 (p\u0026thinsp;=\u0026thinsp;0.917) and Egger\u0026rsquo;s intercept of -0.196 (95% CI: -2.26 to 1.87; p\u0026thinsp;=\u0026thinsp;0.829). Notably, only vertigo\u0026rsquo;s Trim and Fill suggested missing studies (n\u0026thinsp;=\u0026thinsp;2), prompting a re-estimation of the pooled effect, which remained robust (from \u0026minus;\u0026thinsp;2.442 to -2.552). For all other outcomes, the Trim and Fill analysis showed no missing studies. Overall, none of the Egger or Begg tests reached statistical significance, and no corrections were needed except for vertigo, where the adjusted estimate was still within the confidence bounds, supporting the reliability of the meta-analytic findings. These results suggest minimal to no publication bias across the outcomes, strengthening the validity of the observed adverse event rates.\u003c/p\u003e \u003c/div\u003e"},{"header":"4. Discussion","content":"\u003cp\u003eThis comprehensive meta-analysis evaluated the incidence of key AEs related to falls in older patients prescribed AED for neuropathic pain. Six major AEs\u0026mdash;falls, dizziness, somnolence, sedation, vertigo, and ataxia\u0026mdash;were systematically analyzed across 15 studies using fixed-effect and subgroup meta-analytical models, with additional stratification by drug type and dosage. Although the study defines 'older adults' as individuals aged 50 years and above, this threshold was selected to capture a broader at-risk population commonly affected by neuropathic pain and medication-related adverse effects. While this may differ from traditional geriatric age cutoffs (\u0026ge;\u0026thinsp;65 years), the inclusion of this transitional age group enhances the clinical relevance of the findings, particularly in settings where age-related physiological vulnerability begins earlier.\u003c/p\u003e \u003cp\u003eThe overall pooled logit event rate for falls was \u0026minus;\u0026thinsp;1.693 (SE\u0026thinsp;=\u0026thinsp;0.153), indicating a fall incidence of approximately 15.5%, with Gabapentin showing the lowest risk (~\u0026thinsp;10%) and Pregabalin showing a higher fall incidence (~\u0026thinsp;18%). Dizziness was the most common AE, with a pooled incidence of 18.4% (logit \u0026minus;\u0026thinsp;1.483), and Lacosamide exhibiting the highest dizziness risk (~\u0026thinsp;21.6%) along with substantial heterogeneity (I\u0026sup2; = 90.2%). Somnolence and sedation had comparable pooled incidence rates of ~\u0026thinsp;15.9% and ~\u0026thinsp;15.5%, respectively, with highest sedation observed for Pregabalin 600 mg and Gabapentin 1800 mg. Vertigo incidence was ~\u0026thinsp;8% (logit \u0026minus;\u0026thinsp;2.442), with higher rates associated with Carbamazepine and high-dose Gabapentin (\u0026ge;\u0026thinsp;3600 mg). Ataxia was noted in ~\u0026thinsp;13.3% of cases, most significantly with Carbamazepine, Lamotrigine, and Oxcarbazepine. Across all outcomes, heterogeneity was generally low to moderate, suggesting consistent results.\u003c/p\u003e \u003cp\u003eWith fall incidence estimated at approximately 15.5% across RCTs, the results align with observational evidence highlighting AED-related fall risk in older adults. For example, Ensrud et al. (2002) identified a 2.56-fold increased risk of frequent falls among women using anticonvulsants in a large U.S. cohort, while Dustin et al. (2006) similarly reported significantly higher CNS drug use\u0026mdash;including AEDs\u0026mdash;among fall-related outpatient visits in veterans. Masud et al. (2013) extended these findings to men, revealing 2\u0026ndash;3-fold increased fall risks with anticonvulsants, SSRIs, and TCAs. Our RCT-based analysis echoes these associations, particularly noting elevated dizziness and sedation rates with gabapentin and pregabalin, and higher vertigo and ataxia rates at upper therapeutic doses of carbamazepine and lamotrigine. Notably, the pooled RCT data suggest a somewhat lower incidence of vertigo (~\u0026thinsp;8%) and ataxia (~\u0026thinsp;13%) than observational estimates, potentially due to stricter trial inclusion criteria, more controlled dosing, and shorter follow-up periods. Nonetheless, the convergence of evidence reinforces AEDs as key pharmacologic contributors to fall risk, especially when combined with polypharmacy and comorbid frailty. Furthermore, the more favorable AE profiles observed with pregabalin in terms of ataxia, and with lamotrigine in terms of dizziness, corroborate prior reports suggesting improved tolerability with newer AEDs.\u003c/p\u003e \u003cp\u003eThe findings from this meta-analysis are strongly corroborated by extensive observational evidence demonstrating consistent associations between antiepileptic drug use and fall risk in older populations. Multiple systematic reviews have confirmed that AED use in ambulatory older adults leads to significantly increased fall risk, with relative risks ranging from 1.29 to 1.62 and odds ratios from 1.75 to 6.2 (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e). The meta-analysis findings align particularly well with large-scale epidemiological studies, including Ensrud et al.'s prospective cohort of over 8,000 women, which documented a 2.56-fold increased risk of frequent falls among anticonvulsant users (\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e). Similarly, Masud et al.'s cross-sectional study of Danish men aged 60\u0026ndash;75 years reported odds ratios of 2.8 for falls and 2.6 for recurrent falls with AED use (\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e). The observed drug-specific patterns are also supported by real-world evidence, with gabapentin and pregabalin showing dose-dependent associations with altered mental status and falls in haemodialysis patients, where gabapentin demonstrated 50\u0026ndash;55% higher hazards of falls in the highest dose categories(\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e). Furthermore, observational studies in diabetic peripheral neuropathy patients have confirmed that anticonvulsant use significantly increases fall risk (HR 1.34, 95% CI 1.18\u0026ndash;1.51)(\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e), while polypharmacy studies demonstrate that fall risk is particularly elevated when AEDs are combined with other CNS-active medications in frail older adults populations.\u003c/p\u003e \u003cp\u003eA prior systematic review reported an odds ratio of 1.88 (95% CI: 1.02\u0026ndash;3.49) for falls among community-dwelling older adults using AEDs, reinforcing the robustness of our pooled estimate of fall incidence at 15.5% across AED types(\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e). Similarly, de Vries et al. confirmed that both opioids and AEDs are significantly associated with increased fall risk, validating our subgroup findings of drug-specific and dose-dependent fall-related adverse event (AE) profiles (\u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e). Notably, our analysis identified dizziness, somnolence, and sedation as frequent AEs\u0026mdash;mirroring clinical reports where such symptoms are most commonly linked to gabapentin and pregabalin(\u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e). The heterogeneity observed in lacosamide, and gabapentin subgroups may be attributable to such dose variability. For example, pregabalin at 300 mg/day or higher has been shown to result in withdrawal due to AEs in 32% of patients, compared to only 5% in placebo arms(\u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e)\u0026mdash;a pattern closely aligned with our observed dropout-linked AEs. Collectively, these converging lines of evidence underscore the need for individualized prescribing, incorporating careful dose titration, fall-risk screening, and shared decision-making in older patients receiving AEDs for neuropathic pain.\u003c/p\u003e \u003cp\u003eThe findings of our meta-analysis are highly consistent with those reported by Sepp\u0026auml;l\u0026auml; et al. (2018)(\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e), reinforcing the association between AED use and increased fall risk in older adults. Sepp\u0026auml;l\u0026auml; et al.\u0026rsquo;s (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e) pooled analysis demonstrated a significant association between AEDs and fall risk (adjusted OR 1.55; 95% CI: 1.25\u0026ndash;1.92), closely aligning with our estimated fall incidence of approximately 15.5% derived from pooled logit event rates. Notably, both studies highlight opioids and AEDs as high-risk classes, underscoring the critical need for cautious prescribing in geriatric populations. Our dose-stratified analyses further expand on these findings, identifying elevated risks of dizziness, sedation, and ataxia\u0026mdash;particularly at higher AED doses such as gabapentin (\u0026ge;\u0026thinsp;2400 mg) and pregabalin (600 mg). While Sepp\u0026auml;l\u0026auml; et al. (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e) identified substantial heterogeneity across studies, our low heterogeneity supports consistency in specific AED-related adverse event patterns. Together, these findings emphasize the importance of individualized prescribing and comprehensive fall-risk assessment in older adults receiving these medications.\u003c/p\u003e \u003cp\u003eThis study, while comprehensive, has several limitations that warrant consideration. First, despite the inclusion of high-quality randomized controlled trials and observational studies, heterogeneity in study design, population characteristics, and dosing regimens may have introduced residual confounding. The use of varied definitions and reporting formats for adverse events such as dizziness, vertigo, and ataxia across studies may have also affected the comparability and precision of pooled estimates. Second, many included studies reported adverse events only as secondary outcomes, potentially underestimating the true incidence due to underreporting or limited follow-up durations. Third, while the fixed-effects model was appropriate due to overall low heterogeneity, it may not fully capture true variability in drug response across different older adults subgroups, particularly those with polypharmacy or cognitive impairment. Fourth, the analysis was limited to published English-language literature, introducing potential publication and language bias.\u003c/p\u003e \u003cp\u003eFuture research should aim to explore real-world evidence through prospective cohort studies and pragmatic trials focusing on fall-related outcomes as primary endpoints. Dose-response meta-analyses and subgroup evaluations stratified by frailty status, renal function, and co-medication use are essential to understand the individualized risks of AED-related falls. Additionally, mechanistic studies exploring pharmacokinetic and pharmacodynamic changes in the older Adults could inform safer prescribing. Finally, the development and validation of fall-risk prediction tools incorporating drug profiles and geriatric syndromes may support more tailored and safer therapeutic decisions for neuropathic pain management in older adults. These efforts are critical for minimizing harm and improving quality of life in this vulnerable population.\u003c/p\u003e"},{"header":"5. Conclusion","content":"\u003cp\u003eThis comprehensive meta-analysis underscores the significant risk of falls and associated neuropsychiatric adverse events in older patients prescribed AED for neuropathic pain management. The pooled logit event rate for falls was \u0026minus;\u0026thinsp;1.693 (SE\u0026thinsp;=\u0026thinsp;0.153; 95% CI: \u0026minus;\u0026thinsp;1.993 to \u0026minus;\u0026thinsp;1.393), corresponding to a fall incidence of approximately 15.5%, with low heterogeneity (I\u0026sup2; = 0%), indicating consistency across studies. Among specific AEDs, gabapentin demonstrated the lowest fall incidence (~\u0026thinsp;10%) while carbamazepine and lamotrigine were associated with higher risks (~\u0026thinsp;17\u0026ndash;18%). Dizziness, a leading predictor of fall-related morbidity, was reported in 18.4% of patients overall, with particularly high rates in lacosamide (~\u0026thinsp;21.6%) and gabapentin (~\u0026thinsp;19.7%) groups. Similarly, the incidence of somnolence and sedation were notable at ~\u0026thinsp;15.9% and ~\u0026thinsp;15.5%, respectively, further reinforcing the role of AEDs in fall pathophysiology among older adults. Vertigo and ataxia, though less frequently reported (8% and 13.3%, respectively), were significantly associated with high doses of carbamazepine, lamotrigine, and gabapentin.\u003c/p\u003e \u003cp\u003eImportantly, the findings demonstrated dose-dependent increases in adverse event rates, particularly for gabapentin (\u0026gt;\u0026thinsp;1800 mg), pregabalin (\u0026gt;\u0026thinsp;300 mg), and lacosamide (600 mg), supporting the need for cautious titration and individualized therapy. These results highlight the need for routine fall-risk assessments when initiating or escalating AED therapy in geriatric populations. Clinicians should favor agents with lower sedative profiles, apply conservative titration schedules, and consider non-pharmacologic strategies where possible. Ultimately, the study reinforces the critical balance between analgesic benefit and harm mitigation, advocating for a patient-centered approach to neuropathic pain management in older adults.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable. This systematic review and meta-analysis did not involve the use of human participants, human data, or human tissue.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable. The manuscript does not contain data from any individual person.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll data generated or analysed during this study are included in this published article and its supplementary files. Forest plots, risk of bias assessments, and GRADE evidence tables are available within manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNo specific funding was received for this work. The review was conducted as part of the authors’ academic and clinical research development.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors' contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAV\u003c/strong\u003e (Arun Vamadevan, BSc, MPH, PGDTHS): Conceptualisation, Methodology, Data curation, Formal analysis, Investigation, Writing – Original Draft, Project administration, Supervision, Validation.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eVV\u0026nbsp;\u003c/strong\u003e(Dr. Vijesh Vijayan, MD, MRCP, DTM\u0026amp;H): Conceptualisation, Methodology, Data curation, Formal analysis, Investigation, Writing – Original Draft, Project administration, Supervision, Validation.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFM :\u003c/strong\u003e Literature search, screening, and manuscript review.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eNY\u003c/strong\u003e (Nishad Yoosuf, MSc): Data extraction, quality appraisal, and manuscript review.\u003c/p\u003e\n\u003cp\u003eAll authors read and approved the final manuscript. Arun Vamadevan and Dr. Vijesh Vijayan contributed equally and share first authorship. Author order does not reflect seniority.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe would like to thank the NIHR Clinical Research Facility at Liverpool University Hospitals NHS Foundation Trust for supporting the lead author's academic development. We also acknowledge institutional training support from the University of Salford.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors’ information\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAV\u003c/strong\u003e: Postgraduate Researcher (PhD), University of Salford , Matron, NIHR Clinical Research Facility, Liverpool University Hospitals NHS Foundation Trust;.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eVV\u003c/strong\u003e: Senior Clinical Fellow, Stockport NHS Foundation Trust.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eNY\u003c/strong\u003e: Research Scholar, University of Hyderabad.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFM:\u0026nbsp;\u003c/strong\u003eJunior Clinical Fellow, NIHR Clinical Research Facility, Liverpool University Hospitals NHS Foundation Trust, UK\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFootnotes\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNone.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eVan Hecke O, Austin SK, Khan RA, Smith BH, Torrance N (2014) Neuropathic pain in the general population: A systematic review of epidemiological studies. 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Available from: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://pubmed.ncbi.nlm.nih.gov/21320112/\u003c/span\u003e\u003cspan address=\"https://pubmed.ncbi.nlm.nih.gov/21320112/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFreynhagen R, Strojek K, Griesing T, Whalen E, Balkenohl M Efficacy of pregabalin in neuropathic pain evaluated in a 12-week, randomised, double-blind, multicentre, placebo-controlled trial of flexible- and fixed-dose regimens. Pain [Internet]. 2005 Jun [cited 2025 Jun 11];115(3):254\u0026ndash;63. Available from: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://pubmed.ncbi.nlm.nih.gov/15911152/\u003c/span\u003e\u003cspan address=\"https://pubmed.ncbi.nlm.nih.gov/15911152/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Antiepileptic drugs, older adults, Falls, Systematic review, Meta-analysis, Adverse drug reactions","lastPublishedDoi":"10.21203/rs.3.rs-6945897/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6945897/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground:\u003c/strong\u003e\u003cbr\u003e\nOlder adults are at elevated risk of falls, especially when prescribed AED (AEDs) for neuropathic pain. The sedative and neuropsychiatric effects of these agents contribute significantly to fall-related morbidity. However, existing studies often lack stratification by age and dose.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eObjective:\u003c/strong\u003e\u003cbr\u003e\nTo systematically evaluate the incidence and drug-specific risk of falls and fall-related adverse events (AEs) in older adults prescribed AEDs for neuropathic pain.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods:\u003c/strong\u003e\u003cbr\u003e\nA systematic search was performed across PubMed, Scopus, CINAHL, ScienceDirect, and Cochrane Library databases up to May 2025. Studies were selected using PICOS criteria and included RCTs and controlled cohort studies reporting on AED-related AEs among participants aged ≥60 years. The methodological quality was assessed using RoB 2, ROBINS-I, and GRADE frameworks. Meta-analyses were performed using logit event rates and fixed-effects modeling via Comprehensive Meta-Analysis v3.7. Publication bias was evaluated using Begg’s and Egger’s tests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults:\u003c/strong\u003e\u003cbr\u003e\nTwenty-three studies met inclusion criteria. The pooled logit event rate for falls was –1.693 (95% CI: –1.993 to –1.393), corresponding to a 15.5% incidence. Gabapentin showed the lowest fall risk (~10%), while pregabalin and carbamazepine were associated with higher rates of dizziness (up to 21.6%), sedation (~15.5%), and ataxia (~17.8%). Heterogeneity was low (I² = 0–22.3%) across outcomes.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion:\u003c/strong\u003e\u003cbr\u003e\nAEDs carry a clinically significant fall risk in older adults, with dose-dependent patterns. Gabapentin may present a safer profile, while pregabalin and carbamazepine warrant cautious use and monitoring. These findings inform individualized prescribing and fall prevention strategies in geriatric neuropathic pain management.\u003c/p\u003e\n\u003cp\u003ePROSPERO: CRD420251048827\u003c/p\u003e","manuscriptTitle":"Fall-Related Adverse Events of Anti-Epileptic Drugs used for Neuropathic Pain in Older Adults: A systematic Review and Meta-Analysis","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-06-25 07:14:53","doi":"10.21203/rs.3.rs-6945897/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"e4201202-a41d-46c1-b690-5532ae592c8e","owner":[],"postedDate":"June 25th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":50390805,"name":"Clinical Pharmacology"},{"id":50390806,"name":"Geriatrics \u0026 Gerontology"}],"tags":[],"updatedAt":"2025-06-25T07:14:53+00:00","versionOfRecord":[],"versionCreatedAt":"2025-06-25 07:14:53","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-6945897","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6945897","identity":"rs-6945897","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}